Agnese Marsano

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.

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.

PPP3CC gene: a putative modulator of antidepressant response through the B-cell receptor signaling pathway.

Antidepressant pharmacogenetics represents a stimulating, but often discouraging field. The present study proposes a combination of several methodologies across three independent samples. Genes belonging to monoamine, neuroplasticity, circadian rhythm and transcription factor pathways were investigated in two samples (n=369 and 88) with diagnosis of major depression who were treated with antidepressants. Phenotypes were response, remission and treatment-resistant depression. Logistic regression including appropriate covariates was performed. Genes associated with outcomes were investigated in the STAR*D (Sequenced Treatment Alternatives to Relieve Depression) genome-wide study (n=1861). Top genes were further studied through a pathway analysis. In both original samples, markers associated with outcomes were concentrated in the PPP3CC gene. Other interesting findings were particularly in the HTR2A gene in one original sample and the STAR*D. The B-cell receptor signaling pathway proved to be the putative mediator of PPP3CC’s effect on antidepressant response (P=0.03). Among innovative candidates, PPP3CC, involved in the regulation of immune system and synaptic plasticity, seems promising for further investigation.

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.

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.

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.

Il trattamento antidepressivo: effetti sul peso corporeo

SommarioLa depressione maggiore è attualmente la patologia psichiatrica a maggior incidenza nel mondo. La ricerca sui farmaci antidepressivi è in continuo sviluppo, al fine di migliorarne l’efficacia e ridurre al minimo gli effetti collaterali. Uno degli effetti collaterali più comuni con le classi di antidepressivi maggiormente usate attualmente è rappresentato dall’incremento ponderale. Nella pratica clinica è quindi fondamentale monitorare le variazioni di peso associate al trattamento antidepressivo e la diversa potenzialità di ciascun farmaco di provocarlo.

P.2.d.048 COMT modulates working memory and impulsivity control in bipolar disorder

differentiate Bipolar Disorder from Schizophrenia during decision-making. Psychological Medicine 12, 1-10. [2] Brambilla, P., Cerruti, S., Bellani, M., Perlini, C., Ferro, A., Marinelli, Giusto, D., Tomelleri, L., Rambaldelli, G., Tansella, M., Vaibhav A. D., 2011. Shared impairment in associative learning in schizophrenia and bipolar disorder. Progress in Neuro-Psychopharmacology & Biological Psychiatry 35, 1093–1099. [3] Soeiro-de-Souza, M.G., Machado-Vieirab, R., Soares Bioa, D., Martins Do Pradob, C., Alberto Moreno R., 2012 COMT polymorphisms as predictors of cognitive dysfunction during manic and mixed episodes in bipolar I disorder. Bipolar Disorders 14, 554–564. [4] Wirgenes, K.V., Djurovic, S., Sundet, K., Agartz, I., Mattingsdal, M., Athanasiu, L., Melle, I., Andreassen, O.A., 2010 Catechol O-methyltransferase variants and cognitive performance in schizophrenia and bipolar disorder versus controls. Schizophrenia Research 122, 31–37. !

P.1.001 Genes involved in neuroplasticity and short-term response to antidepressant drugs: a complex interplay between genetics and environment

Aim of the study: During the last few years, the ‘neurotrophic model’ has received increasing interest not only as an etiologic hypothesis for psychiatric disorders, but also as an explicative paradigm of the mechanism of action of pharmacological treatments. In particular, it has been hypothesized that genetic differences related to factors involved in CNS neuroplasticity may in part explain individuals’ variation in ADs response. However, both animal and human studies have provided mixed and conflicting results so far, suggesting that the genetic effects related to neuroplastic factors may be moderated by other biological, environmental, and individual factors. The aim of the study is to preliminarily evaluate the interactive effect of Stressful Life Events (SLEs) and genetic variation within two genes involved in neuroplastic processes (BDNF and ST8SIA) on the early response to antidepressant treatment. Methods: The sample was composed of 114 patients affected by Mood or Anxiety disorders, enrolled for treatment with ADs, scoring 8 or more at the Hamilton Rating Scale for Depression score (HAMD), and having filled at the time of recruitment a modified version (selfreport) of the Brown & Harris Stressful Life Events and Difficulties Interview (SLEDS). This modified version allows for investigations into stressful life events (SLEs) at a young age (less than 15 years old), the year before illness onset, and the month preceding current episode. All the patients were evaluated at baseline and weekly thereafter until the fourth week by the Hamilton Rating Scale for Depression (HRSD). Subjects were genotyped for 3 single-nucleotide polymorphisms (SNPs) in BDNF and 5 in ST8SIA. Linkage disequilibrium among SNPs was calculated by Haploview software and haplotypes were obtained by the R-software. The GLM model was employed to test the effect of alleles and haplotypes, crossed with exposure to stress, on % response at follow-up. Results: SLEs did not impact significantly on early response to ADs. Alleles in two SNPs in BDNF (rs11030101 A-allele and rs11030104 G-allele) and alleles in two SNPs in ST8SIA2 (rs11853992-A allele and rs17522085-T) were associated with a slower response to ADs only if not exposed to onset SLEs, whilst they had a similar response to the carriers of the opposite variant if exposed to onset SLEs (allelic analysis: BDNF P< 0.00003; P< 0.00609: ST8SIA P< 0.04; P< 0.033). The BDNF haplotype analysis confirmed this trend (P< 0.00016). Discussion: According to our data, variants in BDNF and ST8SIA may slow down the early response to antidepressants in subjects not exposed to stressors at the illness onset, with a remarkable gene–environment interaction. This results are significant considering that environmental stress is thought to hamper response to AD [1] and the few studies that consider geneenvironment interaction in pharmacological trials usually report a worse response in subjects exposed to stress if they are carriers of specific risk variants (see for example [2]). Nevertheless, the interplay between stress, neuroplasticity, mental distress and pharmacological treatment is far from being clear and deserves further investigation by means of sophisticated methods of investigation.