Genetic signatures of suicide attempt behavior: insights and applications.

INTRODUCTION: Every year about 800,000 complete suicide events occur. The identification of biologic markers to identify subjects at risk would be helpful in targeting specific support treatments. AREA COVERED: A narrative review defines the meta-analytic level of current evidence about the biologic markers of suicide behavior (SB). The meta-analytic evidence gathered so far indicates that the hypothesis-driven research largely failed to identify the biologic markers of suicide. The most consistent and replicated result was reported for: 1) 5-HTR2A T102C, associated with SB in patients with schizophrenia (OR = 1.73 (1.11-2.69)) and 2) BDNF Val66Met (rs6265), with the Met-Val + Val-Val carriers found to be at risk for suicide in the Caucasian population (OR: 1.96 (1.58-2.43)), while Val-Val vs. Val-Met + Met carriers found to be at risk for suicide in the Asian populations (OR: 1.36 (1.04-1.78)). GWAS-based meta-analyses indicate some positive replicated findings regarding the DRD2, Neuroligin gene, estrogen-related genes, and genes involved in gene expression. EXPERT OPINION: Most consistent results were obtained when analyzing sub-samples of patients. Some promising results come from the implementation of the polygenic risk score. There is no current consensus about an implementable biomarker for SB.

Genetics of suicide ideation. A role for inflammation and neuroplasticity?

Suicide is a leading cause of death worldwide. Suicide ideation (SI) is a known risk factor for suicide behaviour (SB). The current psychobiology and genetic predisposition to SI and SB are poorly defined. Despite convincing relevance of a genetic background for SI, there is no current implementable knowledge about the genetic makeup that identifies subjects at risk for it. One of the possible reasons for the absence of a clear-cut evidence is the polygenetic nature of SI along with the very large sample sizes that are needed to observe significant genetic association result. The CATIE sample was instrumental to the analysis. SI was retrieved as measured by the Calgary test. Clinical possible covariates were identified by a nested regression model. A principal component analysis helped in defining the possible genetic stratification factors. A GWAS analysis, polygenic risk score associated with a random forest analysis and a molecular pathway analysis were undertaken to identify the genetic contribution to SI. As a result, 741 Schizophrenic individuals from the CATIE were available for the genetic analysis, including 166,325 SNPs after quality control and pruning. No GWAS significant result was found. The random forest analysis conducted by combining the polygenic risk score and several clinical variables resulted in a possibly overfitting model (OOB error rate < 1%). The molecular pathway analysis revealed several molecular pathways possibly involved in SI, of which those involved in microglia functioning were of particular interest. A medium-small sample of SKZ individuals was analyzed to shed a light on the genetic of SI. As an expected result from the underpowered sample, no GWAS positive result was retrieved, but the molecular pathway analysis indicated a possible role of microglia and neurodevelopment in SI.

Music to improve sleep quality in adults with depression-related insomnia (MUSTAFI): randomized controlled trial.

BACKGROUND: Insomnia in depression is common and difficult to resolve. Unresolved depression-related sleep disturbances increase risk of relapse at high costs for individuals and society. Trials have suggested music for insomnia in various populations, but there is little research on the effectiveness of music for depression-related insomnia. METHODS: We examined the efficacy of a music intervention on insomnia, depression symptoms and quality of life in adults with depression-related insomnia. A two-armed randomized controlled trial was conducted, including depression outpatients with insomnia (n = 112) in a 1:1 ratio to music intervention and waitlist control group. The intervention group listened to music at bedtime for 4 weeks. Participants received treatment as usual during 8 weeks with assessments at baseline, at 4 and 8 weeks. The primary outcome measure was Pittsburgh Sleep Quality Index (PSQI), secondary outcomes comprised Actigraphy, the Hamilton Depression Rating Scale (HAMD-17) and World Health Organisation well-being questionnaires (WHO-5, WHOQOL-BREF). RESULTS: The music intervention group experienced significant improvements in sleep quality and well-being at 4 weeks according to global PSQI scores (effect size = -2.1, 95%CI -3.3; -0.9) and WHO-5 scores (effect size 8.4, 95%CI 2.7;14.0). At 8 weeks, i.e. 4 weeks after termination of the music intervention, the improvement in global PSQI scores had decreased (effect size = -0.1, 95%CI -1.3; 1.1). Actigraphy sleep assessments showed no changes and there was no detection of change in depression symptoms. CONCLUSIONS: Music intervention is suggested as a safe and moderately effective sleep aid in depression-related insomnia. Trial registration: Clinicaltrials.gov. ID NCT03676491.

Body weight changes and bipolar disorder: a molecular pathway analysis.

BACKGROUND: There is evidence suggesting a link between weight-related disorders and bipolar disorder (BD). The pathophysiology of the association includes psychological, social and psychotropic treatment-related variables, together with psychiatric comorbidity. Weight changes during BD may influence compliance to the treatment, quality of life and prognosis, and can modulate risk of death associated with, for example, diabetes or cardiovascular disorders. METHODS: The STEP-BD sample is analyzed through a hypothesis-free molecular pathway analysis in order to detect the molecular pathways that distinguish individuals who experience weight change during BD treatment from those who do not. A total of 618 individuals were available for the analysis, mean age = 41.19 ± 12.58, females = 351 (56.8%). Socioeconomic variables and treatment-related variables were included as clinical covariates. A cluster analysis in the genetic dataset provided the genetic covariate input to the study to avoid stratification factors. RESULT: After applying the quality analysis that is typical for this kind of investigation, no Genome Wide Association Study significant finding was retrieved. Six molecular pathways were found to be significantly associated with weight change during the first 3 months of treatment after correction for multiple testing. Of those, CDC42 (R-HSA-9013148) participates in insulin synthesis and secretion and contributes to the pathogenesis of insulin resistance and Rac Family Small GTPase 1 (R-HSA-9013149) is involved in metabolic regulation of pancreatic islet ß-cells and in diabetes pathophysiology. DISCUSSION: Pathways that are central in energy homeostasis may play a role to separate individuals with BD that will experience weight changes during treatment from those who will not. If confirmed, such finding can be instrumental in the identification of the correct preventive strategies and most correct treatment to increase compliance and efficacy in the treatment of BD.

Enriched developmental biology molecular pathways impact on antipsychotics-induced weight gain.

Psychotropic-induced weight gain (PIWG) may lead to increased risk for cardiovasculardiseases, metabolic disorders and treatment discontinuation. PIWG may be genetically driven. The analysis of complete molecular pathways may grant suffcient power to tackle the biologic variance of PIWG. Such identifcation would help to move a step forward in the direction of personalized treatment in psychiatry. A genetic sample from the CATIE trial (n = 765; M = 556, mean age = 40.93 ± 11.03) treated with diverse antipsychotic drugs was investigated. A molecular pathway analysis was conducted for the identifcation of the molecular pathways enriched in variations associated with PIWG. The developmental biology molecular pathway was signifcantly (P.adj = 0.018) enriched in genetic variations signifcantly (P < 0.01) associated with PIWG. A total of 18 genes were identifed and discussed. The developmental biology molecular pathway is involved in the regulation of ß-cell development, and the transcriptional regulation of white adipocyte differentiation. Results from the current contribution correlate with previous evidence and it is consistent with our earlier result on the STAR*D sample. Furthermore, the involvement of the ß-cell development and the transcriptional regulation of white adipocyte differentiation pathways stress the relevance of the peripheral tissue rearrangement, rather than increased food intake, in the biologic modifcations that follow psychotropic treatment and may lead to PIWG. Further research is warranted.

Molecular pathway analysis associates alterations in obesity-related genes and antipsychotic-induced weight gain.

OBJECTIVE: Antipsychotics often induce excessive weight gain. We hypothesised that individuals with genetic variations related to known obesity-risk genes have an increased risk of excessive antipsychotic-induced weight gain (AIWG). This hypothesis was tested in a subset of the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) trial data set. METHODS: The CATIE trial compared effects and side effects of five different antipsychotics through an 18-month period. Based on the maximum weight gain recorded, excessive weight gain was defined as >7% weight gain. Cytoscape and GeneMANIA were instrumental in composing a molecular pathway from eight selected genes linked to obesity. Genetic information on a total of 495.172 single-nucleotide polymorphisms (SNPs) were available from 765 (556 males) individuals. Enrichment test was conducted through ReactomePA and Bioconductor. A permutation test was performed, testing the generated pathway against 105 permutated pathways (p ≤ 0.05). In addition, a standard genome-wide association study (GWAS) analysis was performed. RESULT: GWAS analysis did not detect significant differences related to excessive weight gain. The pathway generated contained 28 genes. A total of 2067 SNPs were significantly expressed (p < 0.01) within this pathway when comparing excessive weight gainers to the rest of the sample. Affected genes including PPARG and PCSK1 were not previously related to treatment-induced weight gain. CONCLUSIONS: The molecular pathway composed from high-risk obesity genes was shown to overlap with genetics of patients who gained >7% weight gain during the CATIE trial. This suggests that genes related to obesity compose a pathway of increased risk of excessive AIWG. Further independent analyses are warranted that may confirm or clarify the possible reasoning behind.

A molecular pathway analysis stresses the role of inflammation and oxidative stress towards cognition in schizophrenia.

Cognitive processes have a genetic component and are impaired in Schizophrenia (SKZ). The exact nature of such impairment escapes definition. The aim of the present contribution was the identification of the molecular pathways enriched with mutations (SNPs) associated with cognitive performance during antipsychotic treatment. 765 individuals from the CATIE study, males = 559, mean age 40.93 ± 11.03 were included. Working memory and the verbal memory were the evaluated outcomes. A mixed regression model for repeated measures served in R for clinical and molecular pathway analysis. The analysis of quality was conducted under the following criteria: minor allele frequency >0.01, genotype call rate >95%, missing data frequency <5%, Hardy-Weimberg equilibrium threshold >0.0001. The inflation factor was controlled by lambda values. Input for the pathway analysis was SNPs at a p level <0.05 of association genome-wide. Gender, age, education and the duration of the disease were the clinical and socio-demographic variables associated with the cognitive performance. 4268977 SNPs were available after imputation and quality analysis. Pathways related to inflammation and oxidation were the most strongly associated with verbal memory and working memory at a conservative adjusted p value < 0.01. We report that inflammation and in particular the pathway associated with arachidonic acid was enriched in mutations associated with poorer performance at the verbal memory and working memory tasks in SKZ patients.

A model to investigate SNPs' interaction in GWAS studies.

Genome-wide association studies (GWAS) are able to identify the role of individual SNPs in influencing a phenotype. Nevertheless, such analysis is unable to explain the biological complexity of several diseases. We elaborated an algorithm that starting from genes in molecular pathways implicated in a phenotype is able to identify SNP-SNP interaction's role in association with the phenotype. The algorithm is based on three steps. Firstly, it identifies the biological pathways (gene ontology) in which the genes under analysis play a role (GeneMANIA). Secondly, it identifies the group of SNPs that best fits the phenotype (and covariates) under analysis, not considering individual SNP regression coefficients but fitting the regression for the group itself. Finally, it operates an analysis of SNP interactions for each possible couple of SNPs within the group. The sensitivity and specificity of our algorithm was validated in simulated datasets (HapGen and Simulate Phenotypes programs). The impact on efficiency deriving from changes in the number of SNPs/patients under analysis, linkage disequilibrium and minor allele frequency thresholds was analyzed. Our algorithm showed a strong stability throughout all analysis operated, resulting in an overall sensitivity of 81.67 % and a specificity of 98.35 %. We elaborated a stable algorithm that may detect SNPs interactions, especially those effects that pass undetected in classical GWAS. This method may contribute to face the two relevant limitations of GWAS: lack of biological informative power and amount of time needed for the analysis.

A molecular pathway analysis of the glutamatergic-monoaminergic interplay serves to investigate the number of depressive records during citalopram treatment.

The efficacy of current antidepressant (AD) drugs for the treatment of major depressive disorder (MDD) lays behind expectations. The correct genetic differentiation between severe and less severe cases before treatment may pave the way to the most correct clinical choices in clinical practice. Genetics may pave the way such identification, which in turns may provide perspectives for the synthesis of new ADs by correcting the molecular unbalances that differentiate severe and less severe depressive patients. We investigated 1,903 MDD patients from the STAR*D study. Outcome was the number of severe depressive records, defined as a Quick Inventory of Depressive Symptomatology (QIDS)-Clinician rated (C) total score >15, corrected for the number of observations for each patient during the first 14 weeks of citalopram treatment. Predictors were the genetic variations harbored by genes involved in the glutamatergic-monoaminergic interplay as defined in a previous work published by our group. Clinical and socio-demographic stratification factor analyses were taken in cases and controls. Covariated linear regression was the statistical model for the analysis. SNPs were analyzed in groups (molecular pathway analysis) testing the hypothesis that the distribution of significant (p < 0.05) associations between SNPs and the outcome segregates within each pathway/gene subset. The best associated results are relative to two signle SNPs, (rs7744492 in AKAP12 p = 0.0004 and rs17046113 in CAMK2D p = 0.0006) and a molecular pathway (cAMP biosynthetic process p = 0.005). After correction for multitesting, none of them resulted to be significantly associated. These results are consistent with previous findings in literature and further stress that the molecular mechanisms targeted by current ADs may not be the key biological variables that differentiate severe from mild depression.

Genome-wide association study supports the role of the immunological system and of the neurodevelopmental processes in response to haloperidol treatment.

AIM: The aim of the study was to detect the genetic predictors of reseponse to haloperidol. BACKGROUND: Haloperidol is a benchmark drug for the pharmacological treatment of schizophrenia, but the genetics of its efficacy is yet to be elucidated. METHODS: A genome-wide association analysis was carried out in a small sample of patients treated with haloperidol (n=96) and the results were replicated in a larger sample of patients treated with second-generation antipsychotics or perphenazine (final n=169, available from the Clinical Antipsychotic Trials for Intervention Effectiveness study). The Positive and Negative Symptom Scale % score decrease was the outcome in both samples. The period of observation was restricted to 1 month in the replication sample and the most severe cases were included to best balance the replication. The quality control (QC) for the investigation and replication sample included a minor allele frequency at least 0.01, call rate at least 0.95, and Hardy-Weinberg equilibrium P at least 0.0001. The source for imputation was the 1000 Genomes Pilot+HapMap 3 dataset. In total 1 080 870 single nucleotide polymorphisms (SNPs) were available after imputation and QC in the investigation sample. After QC of real genotypes, locus-targeted imputations were restricted to windows of 10 kb on either side of the sentinel SNP in the replication sample. Sentinel SNPs were the most significant findings in the investigation sample. Analysis of variance was the test of choice, PLINK, SNPTEST, and GTOOL were used in the analysis. RESULTS: Two SNPs (rs7912580 and rs2412459) were associated with response in both samples, respectively, located in an intergenic region between the AT-rich interactive domain 5B (ARID5B, MRF1-like) gene and rhotekin 2 (RTKN2) gene, an intronic region located in the eukaryotic translation initiation factor 2α kinase 4 (EIF2AK4) gene (P=1.358e-06 and 0.015 for the Positive and Negative Symptom Scale % total score decrease in the investigation and replication samples, respectively). The direction of association was opposite in the two samples, a finding that is sometimes reported as a flip-flop association. CONCLUSION: Heterozygosis for the ancestral allele was associated with the best improvement in the investigation sample and with poorer outcome in the replication sample. This discrepancy can be because of differences in the replication and investigation sample including the drugs used and the severity at baseline. Nevertheless, this finding is in line with two relevant hypothesis of schizophrenia, related to alterations in the immunological system (RTKN2) and in the neurodevelopment of the central nervous system (EIF2AK4). More studies are warranted to further investigate these associations.

Genetic variations within metalloproteinases impact on the prophylaxis of depressive phases in bipolar patients.

BACKGROUND: The genetic background of the antidepressant response to pharmacological treatment in bipolar disorder (BD) remains elusive. This issue is of primary relevance in that the depressive phases of BD are difficult to treat and they are associated with suicide. AIM: We investigated the role of a set of genetic variations (single-nucleotide polymorphisms) harbored by matrix metalloproteinases (MMPs) as predictors of response to treatment in depressed BD patients. METHODS: 654 BD patients from the publicly available Systematic Treatment Enhancement Program for Bipolar Disorder study were investigated. The outcome was the number of depressive events corrected by the number of times patients were assessed. Clinical and sociodemographic variables were tested as possible stratification factors and included in the analysis if necessary. Genetic predictors were 43 SNPs harbored by 17 MMPs. Imputation, quality check and pruning were conducted according to standards. RESULTS were corrected for multitesting. RESULTS: rs486055 (MMP-10) was associated with the outcome. TT homozygotes had 5.08 ± 3.51 events, CT had 3.47 ± 3.18 and CC had 2.57 ± 2.96 depressive events corrected for the times they had been assessed. The time during which BD patients were observed was not significantly different between the rs486055 genotypes. We found evidence that MMP-10 may be a mediator of the number of depressive phases during BD. Due to the limits of the study including the small-to-medium sample size, the naturalistic design and the possible occurrence of false-positive findings, independent analyses are warranted.

Glutamatergic gene variants impact the clinical profile of efficacy and side effects of haloperidol.

BACKGROUND: The glutamatergic system may be relevant to the pathophysiology of psychosis and to the effects of antipsychotic treatments. OBJECTIVES: We investigated a set of 62 SNPs located in genes coding for subunits of glutamatergic receptors (GAD1, GRIA1, GRIA3, GRIA4, GRID2, GRIK1, GRIK2, GRIK3, GRIK4, GRIN2B, GRM1 and GRM4), and the transporter of glycine (SLC6A5), as modulators of the effects of haloperidol. METHODS AND RESULTS: We studied a sample of 101 acutely ill psychotic patients. We then validated our result in two independent samples from Slovenia (n=71 and n=118) of schizophrenic patients treated with antipsychotics. We both investigated the antipsychotic effect (Positive and Negative Syndrome Scale) and motor side effect (Extrapyramidal Symptom Rating Scale) at baseline and days 3, 7, 14, 21 and 28. SLC6A5 variant (rs2298826) was found to be associated with a rapid rise of motor side effects at the beginning of the treatment (repeated measures of analysis of variance, P=0.0002), followed by a subsequent adaptation, probably dependent on haloperidol doses down titration. A specific effect was noted for dyskinetic symptoms. Haplotype analysis strengthened the relevance of SLC6A5: the C-A-C haplotype (rs1443548, rs883377, rs1945771) was found to be associated with higher Extrapyramidal symptom rating scale scores (overall P=0.01, haplotype P=0.000001). We successfully replicated this finding in the two independent samples from Slovenia. CONCLUSION: This result further stresses the relevance of the glutamatergic system in modulating the effects of haloperidol treatment, especially with regards to motor side effects.

Sociodemographic features predict antidepressant trajectories of response in diverse antidepressant pharmacotreatment environments: a comparison between the STAR*D study and an independent trial.

There is consistent evidence that sociodemographic variables modulate antidepressant response. How the magnitude of such association behaves in different samples and different environments has been poorly investigated. We validated a set of known sociodemographic predictors for trajectories of antidepressant response in both the sequenced treatment alternatives to relieve depression and in an Italian sample. The odds ratios for response were 2.6 and 2.2 (American and Italian, respectively; P = 0.0005 and P = 0.002) for a combination of sociodemographic variables in both groups. This was surprising in that American patients were treated in a variety of specialized or not specialized units widespread in their country, whereas the Italian patients were all inpatients treated in a structure specialized in mood disorders. Thus, we suggest that the environment in which a depressed patient is treated does not significantly affect the association between sociodemographic predictors and response to the pharmacological antidepressant treatment.

Pharmacogenetics of antidepressant response.

Personalized medicine - the adaptation of therapies based on an individual's 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.

The genetics of antipsychotic induced tremors: a genome-wide pathway analysis on the STEP-BD SCP sample.

Extrapyramidal symptoms (EPS) are associated with antipsychotic treatment. The exact definition of the genetic variants that influence the antipsychotic induced EPS would dramatically increase the quality of antipsychotic prescriptions. We investigated this issue in a subsample of the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD). Four hundred nine manic patients were treated with antipsychotics and had complete clinical and genetic data. Outcome was an item of the Clinical Monitoring Form which scored tremors from 0 to 4 at each clinical visit. Visits were scheduled according to clinical issues, based on a naturalistic approach. A genomic inflation factor of 1.017 resulted after genetic quality control. Single SNPs GWAS (Plink) and molecular pathway GWAS were conducted (SNP ratio test, KEGG depository). No single SNP reached GWAS significance level of association. Molecular pathways related to cell survival events and lipid synthesis were significantly associated with antipsychotic induced EPS (P = 0.0009 for Hsa04512, Hsa01031, Hsa00230, Hsa04510, Hsa03320, Hsa04930, and Hsa04115; P = 0.0019 for Hsa04020 and Hsa00561). This finding was consistent with previous GWAS studies.

Suicide Related Phenotypes in a Bipolar Sample: Genetic Underpinnings.

Suicide in Bipolar Disorder (BD) is a relevant clinical concern. Genetics may shape the individual risk for suicide behavior in BD, together with known clinical factors. The lack of consistent replication in BD may be associated with its multigenetic component. In the present contribution we analyzed a sample of BD individuals (from STEP-BD database) to identify the genetic variants potentially associated with three different suicide-related phenotypes: (1) a feeling that the life was not worth living; (2) fantasies about committing a violent suicide; (3) previous attempted suicide. The sample under analysis included 1115 BD individuals. None of the SNPs reached genome-wide significance. However, a trend of association was evidenced for rs2767403, an intron variant of AOPEP gene, in association with phenotype #1 (p = 5.977 × 10-6). The molecular pathway analysis showed a significant enrichment in all the investigated phenotypes on pathways related to post synaptic signaling, neurotransmission and neurodevelopment. Further, NOTCH signaling or the γ-aminobutyric acid (GABA)-ergic signaling were found to be associated with specific suicide-related phenotypes. The present investigation contributes to the hypothesis that the genetic architecture of suicide behaviors in BD is related to alteration of entire pathways rather than single genes. In particular, our molecular pathway analysis points on some specific molecular events that could be the focus of further research in this field.

Pharmacogenetics of antidepressant response: an update.

The past few decades have witnessed much progress in the field of pharmacogenetics. The identification of the genetic background that regulates the antidepressant response has benefited from these advances. This review focuses on the pharmacogenetics of the antidepressant response through the analysis and discussion of the most compelling evidence in this line of research. Online databases (Medline and PsycINFO) have been searched and the most replicated association findings relating to the genetics of the antidepressant response have been reported and discussed. Some replicated findings in the literature have suggested the serotonin transporter promoter (5-HTTLPR), serotonin receptor 1A (HTR1A), serotonin receptor 2A (HTR2A), brain derived neurotrophic factor (BDNF), corticotropin releasing hormone receptor 1 (CRHR1) and FK506 binding protein 5 (FKBP5) as putative regulators of the antidepressant response. A high rate of failure of replication has also been reported. Pharmacogenetics will hopefully provide the basis for personalised antidepressant treatment that is able to maximise the probability of a good response and to minimise side effects; however, this goal is not achievable at the moment. The extent of the validity of the replicated findings and the reasons for the poor results obtained from studies of the pharmacogenetics of the antidepressant response are discussed.

Pharmacogenetics of lithium long-term treatment: focus on initiation and adaptation mechanisms.

Bipolar disorder is a common disease with a high impact in terms of personal suffering and socioeconomic burden. The disentanglement of the molecular deregulations that cause this disorder is pivotal to the understanding of its etiology. This will hopefully cast the engineering of new and more favorable treatments. New insights in the molecular aspects of bipolar disorder may be brought by the understanding of the pharmacodynamics of lithium, the first-line treatment for this disease. The mechanisms by which lithium exerts its activity in the central nervous system are not fully clarified: it is hypothesized that lithium may drive acute molecular events whose activation over time triggers long-lasting modifications in critical neuronal nets. These events are associated with long-lasting changes in the expression profile of genes in neurons that are embedded in these crucial nets. The molecular events that are acutely and chronically triggered by lithium will be reviewed here and matched with the evidence that arises from the pharmacogenetics investigations. Moreover, the pharmacogenetics reports that are not strictly associated with the mechanisms that are thought to be acutely and chronically elicited by lithium will be included in the final part of the paper.

HTR1B as a risk profile maker in psychiatric disorders: a review through motivation and memory.

PURPOSE: Serotonin receptor 1B (HTR1B) is involved in the regulation of the serotonin system, playing different roles in specific areas of the brain. We review the characteristics of the gene coding for HTR1B, its product and the functional role of HTR1B in the neural networks involved in motivation and memory; the central role played by HTR1B in these functions is thoroughly depicted and show HTR1B to be a candidate modulator of the mnemonic and motivationally related symptoms in psychiatric illnesses. METHODS: In order to challenge this assessment, we analyze how and how much the genetic variations located in the gene that codes for HTR1B impacts on the psychiatric phenotypes by reviewing the literature on this topic. RESULTS: We gathered partial evidence arising from genetic association studies, which suggests that HTR1B plays a relevant role in substance-related and obsessive compulsive disorders. On the other hand, no solid evidence for other psychiatric disorders was found. This finding is quite striking because of the heavy impairment of motivation and of mnemonic-related functions (for example, recall bias) that characterize major psychiatric disorders. CONCLUSIONS: The possible reasons for the contrast between the prime relevance of HTR1B in regulating memory and motivation and the limited evidence brought by genetic association studies in humans are discussed, and some suggestions for possible future directions are provided.

TAAR6 variations possibly associated with antidepressant response and suicidal behavior.

Trace amines are putative regulatory elements in the brain whose activity may be relevant to the pathophysiology of depressive episodes. TAAR6 is an orphan receptor probably associated with trace amines. Its genetic variations have been associated with bipolar and schizophrenic disorders. In this study we investigated for the first time the possible association between a set of TAAR6 genetic variations (rs7452939; rs4305745; rs6903874; rs6937506; and rs8192625) with clinical features of depression including antidepressant treatment response in a sample of 187 depressive patients all of Korean origins. rs6903874 T/T carriers had a statistically significant better improvement, and rs6937506 C/C genotype was found to be more frequent in patients without a history of suicide attempt (incomplete or unsuccessful suicide). Haplotype analyses confirmed the association with suicide attempt behavior being haplotype G-T at SNPs rs7452939 and rs6937506 at risk of suicide. These results suggest a possible role of TAAR6 in antidepressant response and suicide behavior in patients with depressive disorder. Heterogeneity of treatment, possible stratification bias not controlled by the statistical analyses, and the risk of false-positive finding mandate further analysis in this direction.