Chiara Fabbri

Meta-analysis of serotonin transporter gene promoter polymorphism (5-HTTLPR) association with antidepressant efficacy.

In the last decade the serotonin transporter gene promoter polymorphism (5-HTTLPR) was likely the most studied genetic variant as predictor of antidepressant response. Nevertheless results are not consistent across studies and previous meta-analysis, since various factors seem to modulate its effect on antidepressant response. With the aim of clarifying this issue, we systematically reviewed literature, selecting 33 studies for an exploratory analysis without any a priori hypothesis. Then we analyzed separately 19 studies performed on Caucasians and 11 on Asians. We tested two phenotypes--remission and response rates--and three genotype comparisons--ll versus ls/ss, ss versus ll/ls and ll versus ss - using the Cochrane review manager. Evaluations were performed separately for SSRIs and mixed/other drugs. Possible clinical modulators were investigated. In the exploratory analysis, we found an association between l allele and l/l genotype and remission. When the analysis was split for ethnic group, in Caucasians we found an association between l allele and both response (OR = 1.58, C.I. 1.16-2.16, p = 0.004), and remission (OR = 1.53, C.I. 1.14-2.04, p = 0.004) in the SSRI group. Only a marginal association between l allele and remission (OR = 1.41, C.I. 1.02-1.95, p = 0.04) survived pooling together mixed antidepressant treatments. In Asians, a small effect of 5-HTTLPR on remission for mixed antidepressants was detected (OR = 2.10, C.I. 1.15-3.84, p = 0.02). Gender, age and age at onset modulated the association in Caucasians. Gender, age and depression severity at baseline modulated the association in Asians. In conclusion, in Caucasians 5-HTTLPR may be a predictor of antidepressant response and remission, while in Asians it does not appear to play a major role.

Pharmacogenetics of antidepressant response

Personalized medicine - the adaptation of therapies based on an individuals genetic and molecular profile - is one of the most promising aspects of modern medicine. The identification of the relation between genotype and drug response, including both the therapeutic effect and side effect profile, is expected to deeply affect medical practice. In this paper, we review the current knowledge about the genes related to antidepressant treatment response and provide methodologic proposals for future studies. We have mainly focused on genes associated with pharmacodynamics, for which a list of promising genes has been identified despite some inconsistency across studies. We have also synthesized the main results for pharmacokinetic genes, although so far they seem less relevant than those for pharmaco dynamic genes. We discuss possible reasons for these inconsistent findings and propose new study designs.

Pharmacogenetics in major depression: a comprehensive meta-analysis.

A number of candidate gene studies focused on major depression (MD) and antidepressant (AD) efficacy have been carried out, but results mainly remain inconclusive. We performed a comprehensive meta-analysis of published candidate gene studies focused on AD efficacy in MD to evaluate the cumulative evidence. A random-effect model was applied to study the polymorphisms with genotypic counts available from at least three independent studies. On the base of previous evidence, the analysis was stratified by ethnicity (Caucasian, Asian, and other/mixed), and AD class (SSRIs and mixed/other ADs). Genotypic data were available for 16 polymorphisms in 11 genes. After the exclusion of 5-HTTLPR in SLC6A4 included in another recent meta-analysis, 15 polymorphisms in 11 genes were included in the present meta-analysis (BDNF rs6265, SLC6A4 STin2, HTR1A rs6295, HTR2A rs6311, rs6313 and rs7997012, HTR6 rs1805054, TPH1 rs1800532, SLC6A2 rs5569, COMT rs4680, GNB3 rs5443, FKBP5 rs1360780 and rs3800373, and ABCB1 rs1045642 and rs2032582). Our results suggested that BDNF rs6265 (Val66Met) heterozygous genotype was associated with better SSRIs response compared to the homozygous genotypes, particularly in Asians (OR=1.53, 95%CI 1.12-2.07, p=0.007). SLC6A4 STin2, HTR2A rs6311 and rs7997012, GNB3 rs5443, FKBP5 rs1360780 and rs3800373, and ABCB1 rs2032582 showed associations with AD efficacy, but these results were highly dependent on one or two single studies. In conclusion, our findings suggested the BDNF Val66Met as the best single candidate involved in AD response, with a selective effect on SSRI treatment. Our overall results supported no major effect of any single gene variant on AD efficacy.

Pharmacogenetics of Antidepressants

Up to 60% of depressed patients do not respond completely to antidepressants (ADs) and up to 30% do not respond at all. Genetic factors contribute for about 50% of the AD response. During the recent years the possible influence of a set of candidate genes as genetic predictors of AD response efficacy was investigated by us and others. They include the cytochrome P450 superfamily, the P-glycoprotein (ABCB1), the tryptophan hydroxylase, the catechol-O-methyltransferase, the monoamine oxidase A, the serotonin transporter (5-HTTLPR), the norepinephrine transporter, the dopamine transporter, variants in the 5-hydroxytryptamine receptors (5-HT1A, 5-HT2A, 5-HT3A, 5-HT3B, and 5-HT6), adrenoreceptor beta-1 and alpha-2, the dopamine receptors (D2), the G protein beta 3 subunit, the corticotropin releasing hormone receptors (CRHR1 and CRHR2), the glucocorticoid receptors, the c-AMP response-element binding, and the brain-derived neurotrophic factor. Marginal associations were reported for angiotensin I converting enzyme, circadian locomotor output cycles kaput protein, glutamatergic system, nitric oxide synthase, and interleukin 1-beta gene. In conclusion, gene variants seem to influence human behavior, liability to disorders and treatment response. Nonetheless, gene × environment interactions have been hypothesized to modulate several of these effects.

Pharmacogenetics of antidepressant drugs: An update after almost 20 years of research

Major depressive disorder (MDD) is an emergent cause of personal and socio‐economic burden, both for the high prevalence of the disorder and the unsatisfying response rate of the available antidepressant treatments. No reliable predictor of treatment efficacy and tolerance in the single patient is available, thus drug choice is based on a trial and error principle with poor clinical efficiency. Among modulators of treatment outcome, genetic polymorphisms are thought to explain a significant share of the inter‐individual variability. The present review collected the main pharmacogenetic findings primarily about antidepressant response and secondly about antidepressant induced side effects, and discussed the main strengths and limits of both candidate and genome‐wide association studies and the most promising methodological opportunities and challenges of the field. Despite clinical applications of antidepressant pharmacogenetics are not available yet, previous findings suggest that genotyping may be applied in the clinical practice. In order to reach this objective, further rigorous pharmacogenetic studies (adequate sample size, study of better defined clinical subtypes of MDD, adequate covering of the genetic variability), their combination with the results obtained through complementary methodologies (e.g., pathway analysis, epigenetics, transcriptomics, and proteomics), and finally cost‐effectiveness trials are required.

Genetic polymorphisms of cytochrome P450 enzymes and antidepressant metabolism

Introduction: The cytochrome P450 (CYP) enzymes are the major enzymes responsible for Phase I reactions in the metabolism of several substances, including antidepressant medications. Thus, it has been hypothesized that variants in the CYP network may influence antidepressant efficacy and safety. Nonetheless, data on this field are still contradictory. The authors aim to give an overview of the published studies analyzing the influence of CYP highly polymorphic loci on antidepressant treatment in order to translate the acquired knowledge to a clinical level. Areas covered: The authors collected and compared experimental works and reviews published from the 1980s to the present and included in the Medline database. The included studies pertain to the effects of CYP gene polymorphisms on antidepressant pharmacokinetic parameters and clinical outcomes (response and drug-related adverse effects), with a focus on applications in clinical practice. The authors focused mainly on in vivo studies in humans (patients or healthy volunteers). Expert opinion: Great variability in antidepressant metabolism among individuals has been demonstrated. Thus, with the current interest in individualized medicine, several genetic tests to detect CYP variants have been produced. They provide a potentially useful way to anticipate some clinical outcomes of antidepressant treatment, although they will only be extensively used in clinical practice if precise and specific treatment options and guidelines based on genetic tests can be provided.

Mechanisms of antidepressant action: an integrated dopaminergic perspective.

The molecular mechanisms that cause and maintain the major depressive disorder (MDD) are currently unknown. Consistently, antidepressant treatments are characterized by insufficient success rates. This causes high social costs and severe personal sufferings. In the present review we analyze some of the paradigms that are used to explain MDD, particularly from the perspective of the dopaminergic (DA) system. DA has been more classically associated with psychosis and substance abuse disorders, even though a role of DA in MDD has been proposed as well and some antidepressants with DA profile exist. In the present work, we review some of the molecular mechanisms that underpin MDD from the perspective of the dopaminergic system, in the hope of unifying some of the major theories of MDD - the monoaminergic, inflammatory, epigenetics, neurotrophin and anti-apoptotic theories. Several shared components of these theories are highlighted, partially accounted by the functions of the DA system (see supplementary video).

From Pharmacogenetics to Pharmacogenomics: The Way toward the Personalization of Antidepressant Treatment

Objective: Major depressive disorder is the most common psychiatric disorder, worldwide, yet response and remission rates are still unsatisfactory. The identification of genetic predictors of antidepressant (AD) response could provide a promising opportunity to improve current AD efficacy through the personalization of treatment. The major steps and findings along this path are reviewed together with their clinical implications and limitations. Method: We systematically reviewed the literature through MEDLINE and Embase database searches, using any word combination of “antidepressant,” “gene,” “polymorphism,” “pharmacogenetics,” “genome-wide association study,” “GWAS,” “response,” and “adverse drug reactions.” Experimental works and reviews published until March 2012 were collected and compared. Results: Numerous genes pertaining to several functional systems were associated with AD response. The more robust findings were found for the following genes: solute carrier family 6 (neurotransmitter transporter), member 4; serotonin receptor 1A and 2A; brain-derived neurotrophic factor; and catechol-O-methyltransferase. Genome-wide association studies (GWASs) provided many top markers, even if none of them reached genome-wide significance. Conclusions: AD pharmacogenetics have not produced any knowledge applicable to routine clinical practice yet, as results were mainly inconsistent across studies. Despite this, the rising awareness about methodological deficits of past studies could allow for the identication of more suitable strategies, such as the integration of the GWAS approach with the candidate gene approach, and innovative methodologies, such as pathway analysis and study of depressive endophenotypes.

Shared genetics among major psychiatric disorders.

Since 2005, the National Human Genome Research Institute database of published genome-wide association studies (GWAS) has accumulated more than 5110 entries for over 500 traits. The rapid growth of data repositories has enabled researchers to undertake large studies and meta-analyses, and has increased the power for detection of trait-associated variants. In The Lancet, the Psychiatric Genomics Consortium (PGC) describes its analysis of genome-wide single nucleotide polymorphism (SNP) data for 33 332 cases and 27 888 controls distributed among the fi ve major psychiatric disorders in the PGC (major depressive disorder, bipolar disorder, schizophrenia, autism spectrum disorders, and attention defi cit hyper activity disorder). The study has combined some of the leading methodological approaches in genetics to examine the possibility of shared genetic make-up for these diseases. The main innovative contribution of the present study is the combination of qualitative and quantitative analyses of the shared genetic features associated with vulnerability to these fi ve disorders. Reliability of the results was strengthened by an accurate methodological design. The investigators addressed some typical limitations of GWAS (cryptic population stratifi cation and unknown biological relevance of the detected variants) by inclusion of several case-control samples, all of European ancestry, and by corroboration of results by pathway and expression quantitative trait loci (eQTL) analysis. Pathway analy sis might balance genetic heterogeneity bias (ie, the analysis of a whole molecular pathway avoids spurious associations due to simple interpopulation and intrapopulation individual allele stratifi cation) and eQTL corroborated genetic fi ndings at the functional level; both techniques are crucial to confi rmation of the hypothesis-free results of GWAS. Because the unit of analysis is set to functionally interacting molecules, pathway analysis also reduces the risk of type 2 error. Indeed, although individual SNP markers did not reach signifi cance in many GWAS, ranking of SNPs associated previously with diff erent psychiatric disorders identifi ed convergence of pathways in synaptogenesis, axonal guidance, and synaptic plasticity, and now calcium signalling, which is pivotal in the mechanisms of all these biological processes. Nevertheless, genetic eff ects with odds ratios around 1 are diffi cult to disentangle from cryptic population stratifi cation, thus deep sequencing of the top regions in homogeneous populations would be appropriate for confi rmation of these fi ndings. The design of the present study ensures the collection of a large sample with some degree of diagnostic reliability, but data for patients were obtained only with use of general disease categories; substantial clinical heterogeneity is expected, which could lead to a high risk of missing markers showing genuine associations. In addition to methodological issues which are pertinent to researchers, genetic studies should provide translational value for clinicians. With this perspective, the present study might contribute to future nosographic systems, which could be based not only on statistically determined clinical categories, but also on biological pathogenic factors that are pivotal to the identifi cation of suitable treatments. Consistent with the present results, voltage-dependent calcium channel antagonists produce antidepressant-like eff ects

Prevalence and risk factors of extrapancreatic malignancies in a large cohort of patients with intraductal papillary mucinous neoplasm (IPMN) of the pancreas

BACKGROUND The objectives of this study are to estimate prevalence and incidence of extrapancreatic malignancies (EPMs) among intraductal papillary mucinous neoplasms (IPMNs) of the pancreas, and to identify risk factors for their occurrence. PATIENTS AND METHODS We conducted multicentric cohort study in Italy from January 2010 to January 2011 including 390 IPMN cases. EPMs were grouped as previous, synchronous (both prevalent) and metachronous (incident). We calculated the observed/expected (O/E) ratio of prevalent EPMs, and compared the distribution of demographic, medical history and lifestyle habits. RESULTS Ninety-seven EPMs were diagnosed in 92 patients (23.6%), among them 78 (80.4%) were previous, 14 (14.4%) were synchronous and 5 (5.2%) were metachronous. O/E ratios for prevalent EPMs were significantly increased for colorectal carcinoma (2.26; CI 95% 1.17-3.96), renal cell carcinoma (6.00; CI 95% 2.74-11.39) and thyroid carcinoma (5.56; CI 95% 1.80-12.96). Increased age, heavy cigarette smoking, alcohol consumption and first-degree family history of gastric cancer are significant risk factors for EPMs, while first-degree family history of colorectal carcinoma was borderline. CONCLUSION We report an increased prevalence of EPMs in Italian patients with IPMN, especially for colorectal carcinoma, renal cell and thyroid cancers. A systematic surveillance of IPMN cases for such cancer types would be advised.BACKGROUND The objectives of this study are to estimate prevalence and incidence of extrapancreatic malignancies (EPMs) among intraductal papillary mucinous neoplasms (IPMNs) of the pancreas, and to identify risk factors for their occurrence. PATIENTS AND METHODS We conducted multicentric cohort study in Italy from January 2010 to January 2011 including 390 IPMN cases. EPMs were grouped as previous, synchronous (both prevalent) and metachronous (incident). We calculated the observed/expected (O/E) ratio of prevalent EPMs, and compared the distribution of demographic, medical history and lifestyle habits. RESULTS Ninety-seven EPMs were diagnosed in 92 patients (23.6%), among them 78 (80.4%) were previous, 14 (14.4%) were synchronous and 5 (5.2%) were metachronous. O/E ratios for prevalent EPMs were significantly increased for colorectal carcinoma (2.26; CI 95% 1.17-3.96), renal cell carcinoma (6.00; CI 95% 2.74-11.39) and thyroid carcinoma (5.56; CI 95% 1.80-12.96). Increased age, heavy cigarette smoking, alcohol consumption and first-degree family history of gastric cancer are significant risk factors for EPMs, while first-degree family history of colorectal carcinoma was borderline. CONCLUSION We report an increased prevalence of EPMs in Italian patients with IPMN, especially for colorectal carcinoma, renal cell and thyroid cancers. A systematic surveillance of IPMN cases for such cancer types would be advised.