[Potential benefits and limitations of new technologies in the personalized treatment of depression]. / Potenzialità e limiti delle nuove tecnologie nella terapia personalizzata della depressione.

While for other complex disorders like cancer a limited number of markers are at hand, there are currently no biomarkers available for major depression. A major goal is therefore the identification of biomarkers that can categorize subsets of patients in a consistent manner. Biomarkers for mood disorders provides discovery strategies from scientists in academia and pharma and biotech industries. This will allow a more precise definition of psychiatric disorders and in turn facilitate investigations of the pathophysiology and enhance the ability for patient treatment. Moreover, pharmacogenomics is a new area of medicine that uses the data emerging from the sequencing of the human genome to predict drug responses and to identify new targets for treatment. Pharmacogenomics is of particular relevance to depression, which is a common and complex disorder of unknown cause for which prediction of treatment response and identification of new targets for therapeutics is of crucial importance. Depression represents major health problems in the 21 st century, and is major causes of disability. The fundamental biological mechanisms underlying the effects of psychopharmacological treatments are unknown. Pharmacogenomic approaches to psychiatric disorders offer the possibility to identify a network of genes that may underlie the mechanisms of psychotropic drugs, and the possibility of identifying groups of individuals who are more likely to respond to specific drugs or to suffer from side effects. Such efforts will lead to novel therapeutic targets for drug development and to the individualization of treatment, maximizing the likelihood of positive therapeutic outcomes. In this paper we review studies that has been focused on the prediction of antidepressants response based on genotype. We will also address the methodological issues that are emerging in the context of clinical pharmacogenomic and biomarker's investigation.

Understanding the role of personality and alexithymia in food preferences and PROP taste perception.

Taste perception and food preferences are influenced by a variety of factors, including personality characteristics. The aims of this study were to examine the role of personality characteristics, such as alexithymia (a personality construct characterized by inability to identify, describe, and work with one's own feelings), in: 1) taste responses to the bitter genetic taste-marker PROP and 2) food liking. We studied 649 healthy subjects residing in six genetically-isolated villages of Northeast Italy. Data on PROP taste responsiveness, food liking, personality characteristics and TAS2R28 genotypes were collected. Results showed that PROP non-tasters had higher alexithymia scores than PROP tasters. Moreover, the presence of alexithymia in heterozygous individuals for the rs1726886 polymorphism of the TAS2R38 gene was associated with a reduction in the perceived intensity of PROP. Finally, higher alexithymia scores were associated with liking of alcohol, sweets and fats/meats whereas lower alexithymia scores were related to liking of vegetables, condiments and strong cheeses, Measures of temperament, character, anxiety and depression were also related to food liking. Our findings suggest that: 1) alexithymia, in addition to the TAS2R38 polymorphism, may play a role in responsiveness to the aversive and bitter taste of PROP; and 2) alexithymia, in combination with other personality traits, may provide important insights for better understanding food liking.

Analysis of functional variants reveals new candidate genes associated with alexithymia.

In this study we explored the possible association between 36,915 functional variants and alexithymia, a personality trait characterized by the inability to identify and describe emotions and feelings. From our analysis, variants in the genes ABCB4, TP53AIP1, ARHGAP32 and TMEM88B were identified linked to the alexithymia phenotype.

Brain-derived neurotrophic factor serum levels in genetically isolated populations: gender-specific association with anxiety disorder subtypes but not with anxiety levels or Val66Met polymorphism.

Anxiety disorders (ADs) are disabling chronic disorders with exaggerated behavioral response to threats. This study was aimed at testing the hypothesis that ADs may be associated with reduced neurotrophic activity, particularly of Brain-derived neurotrophic factor (BDNF), and determining possible effects of genetics on serum BDNF concentrations. In 672 adult subjects from six isolated villages in North-Eastern Italy with high inbreeding, we determined serum BDNF levels and identified subjects with different ADs subtypes such as Social and Specific Phobias (PHSOC, PHSP), Generalized Anxiety Disorder (GAD), and Panic Disorder (PAD). Analysis of the population as a whole or individual village showed no significant correlation between serum BDNF levels and Val66Met polymorphism and no association with anxiety levels. Stratification of subjects highlighted a significant decrease in serum BDNF in females with GAD and males with PHSP. This study indicates low heritability and absence of any impact of the Val66Met polymorphism on circulating concentrations of BDNF. Our results show that BDNF is not a general biomarker of anxiety but serum BDNF levels correlate in a gender-specific manner with ADs subtypes.

Is altered BDNF biosynthesis a general feature in patients with cognitive dysfunctions?

Severe cognitive deficits are a frequent outcome of both neurodegenerative and neurodevelopmental disorders. In the attempt to define new clinical biomarkers, current research trends aim at the identification of common molecular features in these pathologies rather than searching for differences. Brain-derived neurotrophic factor (BDNF) has attracted great interest as possible biomarker because of its key role in synaptic remodeling during cognitive processes. BDNF undergoes proteolytic processing and studies in animal models have highlighted that different forms of learning and memory require either the proBDNF precursor or the mature BDNF form. Significantly, an altered expression of BDNF forms was found in postmortem brains and serum from patients with schizophrenia, Alzheimer's disease and mood disorders. Based on these studies, this review puts forward the hypothesis that abnormalities in proBDNF or mBDNF biosynthesis may correspond to different cognitive dysfunctions in these brain diseases, while the role of truncated BDNF remains unknown.

Toward a unified biological hypothesis for the BDNF Val66Met-associated memory deficits in humans: a model of impaired dendritic mRNA trafficking.

Brain-derived neurotrophic factor (BDNF) represents promotesa key molecule for the survival and differentiation of specific populations of neurons in the central nervous system. BDNF also regulates plasticity-related processes underlying memory and learning. A common single nucleotide polymorphism (SNP) rs6265 has been identified on the coding sequence of human BDNF located at 11p13. The SNP rs6265 is a single base mutation with an adenine instead of a guanine at position 196 (G196A), resulting in the amino acid substitution Val66Met. This polymorphism only exists in humans and has been associated with a plethora of effects ranging from molecular, cellular and brain structural modifications in association with deficits in social and cognitive functions. To date, the literature on Val66Met polymorphism describes a complex and often conflicting pattern of effects. In this review, we attempt to provide a unifying model of the Val66Met effects. We discuss the clinical evidence of the association between Val66Met and memory deficits, as well as the molecular mechanisms involved including the reduced transport of BDNF mRNA to the dendrites as well as the reduced processing and secretion of BDNF protein through the regulated secretory pathway.

Low serum truncated-BDNF isoform correlates with higher cognitive impairment in schizophrenia.

Brain-derived neurotrophic factor (BDNF) is a key factor in learning and memory. Altered BDNF-signalling is thought to contribute to the pathogenesis of schizophrenia (SZ) especially in relation to cognitive deficits. However, analysis of serum BDNF as a potential biomarker in schizophrenia has provided controversial data. We hypothesized that these confounding results might be due to a differential regulation of BDNF precursor pro-BDNF (32 KDa) and proteolytic products mature (mat-BDNF; 14 KDa), and truncated-BDNF (28 KDa). Accordingly, we investigated the serum abundance of these BDNF isoforms and its relationship with cognitive impairment in schizophrenia. Schizophrenia was diagnosed with PANSS test. Abbreviated cognitive assessment included tests for attention, perceptual-motor skills, processing speed and memory. Using an ELISA assay, we found a slight reduction in serum BDNF levels in SZ patients (n = 40) with respect to healthy controls (HC, n = 40; p = 0.018). Western-blot analysis revealed increased serum pro-BDNF and mat-BDNF and reduced truncated-BDNF (p < 0.001) in SZ with respect to HC. Patients with an increase in pro-BDNF (n = 15/40) or mat-BDNF (n = 9/40) higher than the HC mean + 2 Standard Deviations (SD) also had >2SD reduction of truncated-BDNF (n = 27/40). Reduced truncated-BDNF correlated significantly with higher positive and lower negative PANNS scores and a worst performance in all cognitive assays but not with antipsychotic type. Measurement of serum truncated-BDNF abundance predicted for high cognitive deficits with sensitivity = 67.5%, specificity = 97.5%, Negative Predictive Value = 75% and Positive Predictive Value = 96.4%. These results suggest deficiency in pro-BDNF processing as a possible biological mechanism underlying schizophrenia with cognitive impairment.

Repeated suicidal behaviour: Stressful life events and 5-HTTLPR genetic polymorphism.

Stressful life events and dysregulated mono-aminergic neurotransmission have been associated with suicidal behaviour. The aim of this investigation was to analyze suicidal behaviour in multiple attempters in relation to the stressful life events, and to the polymorphism of the serotonin transporter (SERT) gene. Multiple suicide attempters, admitted to the University Psychiatric Clinic, were interviewed for the number of previous suicide attempts and for the occurrence of stressful life events, recorded in a Life History Calendar. The patients were further genotyped for 5-HTTLPR polymorphism of SERT. The number of suicide attempts was found to be significantly correlated with the number of negative life events experienced during the 6 months preceding each suicide attempt. The L/L genotype was associated with a reduced number of multiple suicide attempts. These results should prompt future study with a larger number of subjects to further investigate the interaction of genetic and environmental factors in repeated suicidal behaviour.