Genetic underpinnings of YMRS and MADRS scores variations in a bipolar sample.

Bipolar disorder (BPD) affects approximately 2% of the global population. Its clinical course is highly variable and current treatments are not always effective for all patients. Genetic factors play a significant role in BPD and its treatment, although the genetic background appear to be highly heterogeneous. Polygenic risk scores (PRS) are a powerful tool for risk assessment, yet using all genomic data may introduce confounding factors. Focusing on specific genetic clusters PRS (gcPRS) may mitigate this issue. This study aims to assess a neural network model's efficacy in predicting response to treatment (RtT) in BPD individuals using PRS calculated from specific gcPRS and other variables. 1538 individuals from STEP-BD (age 41.39 ± 12.66, 59.17% female) were analyzed. gcPRS were calculated from a Genome-wide association study (GWAS) with clinical covariates and a molecular pathway analysis (MPA) based on drugs interaction networks. A neural network was trained using gcPRS and clinical variables to predict RtT. Ten biological networks were identified through MPA, with gcPRS derived from risk variants within corresponding gene groups. However, the model did not show significant accuracy in predicting RtT in BPD individuals. RtT in BPD is influenced by multiple factors. This study attempted a comprehensive approach integrating clinical and biological data to predict RtT. However, the model did not achieve significant accuracy, possibly due to limitations such as sample size, disorder complexity, and population heterogeneity. This data highlights the challenge of developing personalized treatments for BPD and the necessity for further research in this area.

The Role of Nanotechnologies in Brain Tumors.

The treatment of glioma remains one of the most interesting topics in neurooncology. Glioblastoma multiforme is the most aggressive and prevalent malignant brain tumor. Nowadays, technologies and new tools are helping the neurosurgeons to define a tailored surgery. However, there are few pharmaceutical strategies in operated and nonoperated patients. There are still few anticancer drugs approved by FDA and EMA. Moreover, these drugs are not so effective and have a lot of side effects due to their toxicity. Nanoparticles are a new strategy which could help to create and carry new drugs. In fact, NPs improve the pharmacokinetic properties of anticancer drugs, reduce side-effects, and increase drug half-life and its selectivity. Nanoparticle drug delivery system has been studied for targeting different molecular biomarkers and signaling pathways. Furthermore, the first problem of anticancer drugs in the treatment of gliomas is penetrating the blood brain barrier which represents an insurmountable wall for most of synthetic and natural particles. In the last 15 years, a lot of researches tried to design a perfect nanoparticle both able to cross blood-brain barrier and to selectively target glioma cells, unfortunately, without great results. In vivo human trials are still ongoing and many of them have already failed. In this chapter we evaluate the effectiveness of nanotechnologies in the treatment of brain tumors. There is not yet, currently, a nanoparticle drug designed for the treatment of gliomas approved by FDA and EMA. Advancements in discovery of molecular characteristics of tumors lead to the development of targeted nanoparticles that are tested in numerous in vitro and in vivo studies on gliomas. Novel and repurposed drugs, as well as novel drug combinations, have also been already studied but those are not included in this chapter because the carried drugs (active substances) are not included among the approved anticancer drug used in the treatment of gliomas.

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.

Psychiatric disorders and SLC6A4 gene variants: possible effects on alcohol dependence and alzheimer's disease.

Serotoninergic system is one of the most important neurotransmission systems investigated in the field of psychiatry. Extensive evidence reveals how alterations of this system, and especially of the SLC6A4 gene, may be associated with psychiatric disorders. In this study we aimed to evaluate the pleiotropic nature of SLC6A4 alterations and their association with the overall risk of brain diseases rather than disorder-specific. SLC6A4 variants, namely 5HTTLPR, STin2, rs2066713, rs25531, rs4251417, rs6354 and rs7224199 were investigated in 4 independent cohorts of subjects with specific psychiatric disorders, including Alcohol dependence disorder (ALC), Alzheimer disease (ALZ), Schizophrenia (SCZ) and Bipolar disorder (BPD). Other variables (biochemical parameters and Psychiatric scales scores) were also tested for association. SLC6A4 polymorphisms are not associated with the risk of developing major psychiatric disorders (SCZ and BPD); however some signals were detected in ALC (HTTLPR pd = 9.25 × 10-03, pr = 7.24 × 10-03; rs2066713 pd = 6.35 × 10-08; rs25531 pd = 2.95 × 10-02; rs4251417 pd = 2.46 × 10-03), and ALZ (rs6354 pr = 1.22 × 10-02; rs7224199 pd = 1.00 × 10-08, pr = 2.65 × 10-02) cohorts. Some associations were also observed on exploratory analyses. Our findings did not reveal any major influence on SCZ and BPD development; On the other hand, some alteration of the SLC6A4 sequence were associated with an increased risk of ALC and ALZ disorders, suggesting common pathways. The results of this study should be carefully interpreted since it suffers of some inherent limitations (e.g. cohort size, slight ethnic heterogeneity). Further analyses may provide better detail on the molecular processes behind SLC6A4 alterations.

Correction to: Psychiatric disorders and SLC6A4 gene variants: possible effects on alcohol dependence and alzheimer's disease.

The following authors have double affiliations: Stefania Boccia, Marco Di Nicola and they should read.

FKBP5 Gene Variants May Modulate Depressive Features in Bipolar Disorder.

BACKGROUND: Previous evidence suggested the possible association of FK506 binding protein 5 (FKBP5) gene variants in bipolar disorder (BPD). OBJECTIVE: Given the need of refinement of the findings obtained in large but poorly phenotyped samples, this study investigated the possible role of variants within FKBP5 in a small but deeply phenotyped BPD sample. METHODS: A sample (N = 131) of bipolar patients were investigated with 10 polymorphisms within the FKBP5 gene. A control sample (N = 65) was also used for the analyses. Treatment response and remission of symptoms were evaluated using of the Hamilton Depression Rating Scale (HDRS), Hamilton Anxiety Rating Scale (HARS), and Young Mania Rating Scale (YMRS). The same analyses were also performed on the depressive subsample of BPD (D.BPD). RESULTS: rs3800373 was associated with disorder risk in the depressive BPD subsample with the G allele being more frequent in subjects with a D.BPD phenotype. This was the only association that survived statistical correction. CONCLUSIONS: rs3800373 FKBP5 may increase the risk of developing predominantly depressed BPD, probably through the creation of an enhancer consensus sequence in the 3'UTR of the gene, thus potentially increasing its expression. This finding seems to be partially supported by literature data, which evidenced increased levels of FKBP5 in psychiatric subjects.

Alzheimer's Disease and Neurotransmission Gene Variants: Focus on Their Effects on Psychiatric Comorbidities and Inflammatory Parameters.

BACKGROUND: Alzheimer's disease (AD) is a neurodegenerative disorder accounting for 60-70% of dementia cases. Genetic origin accounts for 49-79% of disease risk. This paper aims to investigate the association of 17 polymorphisms within 7 genes involved in neurotransmission (COMT, HTR2A, PPP3CC, RORA, SIGMAR1, SIRT1, and SORBS3) and AD. METHODS: A Greek and an Italian sample were investigated, for a total of 156 AD subjects and 301 healthy controls. Exploratory analyses on psychosis and depression comorbidities were performed, as well as on other available clinical and serological parameters. RESULTS: AD was associated with rs4680 within the COMT gene in the total sample. Trends of association were found in the 2 subsamples. Some nominal associations were found for the depressive phenotype. rs10997871 and rs10997875 within SIRT1 were nominally associated with depression in the total sample and in the Greek subsample. rs174696 within COMT was associated with depression comorbidity in the Italian subsample. DISCUSSION: Our data support the role of COMT, and particularly of rs4680, in the pathogenesis of AD. Furthermore, the SIRT1 gene seems to modulate depressive symptomatology in the AD population.

Neuroplasticity and second messenger pathways in antidepressant efficacy: pharmacogenetic results from a prospective trial investigating treatment resistance.

Genes belonging to neuroplasticity, monoamine, circadian rhythm, and transcription factor pathways were investigated as modulators of antidepressant efficacy. The present study aimed (1) to replicate previous findings in an independent sample with treatment-resistant depression (TRD), and (2) to perform a pathway analysis to investigate the possible molecular mechanisms involved. 220 patients with major depressive disorder who were non-responders to a previous antidepressant were treated with venlafaxine for 4-6 weeks and in case of non-response with escitalopram for 4-6 weeks. Symptoms were assessed using the Montgomery Asberg Depression Rating Scale. The phenotypes were response and remission to venlafaxine, non-response (TRDA) and non-remission (TRDB) to neither venlafaxine nor escitalopram. 50 tag SNPs in 14 genes belonging to the pathways of interest were tested for association with phenotypes. Molecular pathways (KEGG database) that included one or more of the genes associated with the phenotypes were investigated also in the STAR*D sample. The associations between ZNF804A rs7603001 and response, CREB1 rs2254137 and remission were replicated, as well as CHL1 rs2133402 and lower risk of TRD. Other CHL1 SNPs were potential predictors of TRD (rs1516340, rs2272522, rs1516338, rs2133402). The MAPK1 rs6928 SNP was consistently associated with all the phenotypes. The protein processing in endoplasmic reticulum pathway (hsa04141) was the best pathway that may explain the mechanisms of MAPK1 involvement in antidepressant response. Signals in genes previously associated with antidepressant efficacy were confirmed for CREB1, ZNF804A and CHL1. These genes play pivotal roles in synaptic plasticity, neural activity and connectivity.

CCM3/SERPINI1 bidirectional promoter variants in patients with cerebral cavernous malformations: a molecular and functional study.

BACKGROUND: Cerebral cavernous malformations (CCMs) are vascular anomalies of the nervous system mostly located in the brain presenting sporadically or familial. Causes of familial forms are mutations in CCM1 (Krit1), CCM2 (MGC4607) and CCM3 (PDCD10) genes. Sporadic forms with no affected relative most often have only one lesion and no germ line mutations. However, a number of sporadic cases with multiple lesions have been reported and are indeed genetic cases with a de novo mutation or a mutation inherited from an asymptomatic parent. METHODS: Here, we performed an analysis of regulatory region of CCM genes in 60 sporadic patients, negative for mutations in coding region and intron-exon boundaries and large deletion/duplications in CCM genes by direct sequencing and MLPA. Among 5 variants identified in 851-bp region shared by CCM3 and SERPINI1 genes and acting as asymmetric bidirectional promoter, two polymorphisms c.-639 T > C/rs9853967 and c.-591 T > C/rs11714980 were selected. A case-control study was performed to analyze their possible relationships with sporadic CCMs. Promoter haplotypes activities on CCM3/SERPINI1 genes expression were tested by dual-luciferase assay. RESULTS: No variants were identified in CCM1 and CCM2 regulatory regions. In CCM3/SERPINI1 asymmetric bidirectional promoter 5 variants, 2 of them unknown and 3 corresponding to polymorphisms c.-639 T > C/rs9853967, c.-591 T > C/rs11714980 and c.-359G > A/rs9834676 were detected. While rs9853967 and rs11714980 polymorphisms fall in a critical regulatory fragment outside the minimal promoter in intergenic region, other variants had no effects on transcription factor binding according to RegRNA tool. Case-control study performed on 60 patients and 350 healthy controls showed frequencies of the mutated alleles significantly higher in the control group than in patients. Furthermore, the functional assay showed a significant reduction of CCM3 expression for C-C haplotype even more than for T-C and C-T haplotypes. In SERPINI1 direction, the reduction was not statistically significant. CONCLUSIONS: Our data indicated that rs9853967 and rs11714980 polymorphisms could be associated with a protective role in CCM disease.

Genes Involved in Neurodevelopment, Neuroplasticity, and Bipolar Disorder: CACNA1C, CHRNA1, and MAPK1.

BACKGROUND: Bipolar disorder (BPD) is a common and severe mental disorder. The involvement of genetic factors in the pathophysiology of BPD is well known. In the present study, we tested the association of several single-nucleotide polymorphisms (SNPs) within 3 strong candidate genes (CACNA1C, CHRNA7, and MAPK1) with BPD. These genes are involved in monoamine-related pathways, as well as in dendrite development, neuronal survival, synaptic plasticity, and memory/learning. METHODS: One hundred and thirty-two subjects diagnosed with BPD and 326 healthy controls of Korean ancestry were genotyped for 40 SNPs within CACNA1C, CHRNA17, and MAPK1. Distribution of alleles and block of haplotypes within each gene were compared in cases and controls. Interactions between variants in different loci were also tested. RESULTS: Significant differences in the distribution of alleles between the cases and controls were detected for rs1016388 within CACNA1C, rs1514250, rs2337980, rs6494223, rs3826029 and rs4779565 within CHRNA7, and rs8136867 within MAPK1. Haplotype analyses also confirmed an involvement of variations within these genes in BPD. Finally, exploratory epistatic analyses demonstrated potential interactive effects, especially regarding variations in CACNA1C and CHRNA7. LIMITATIONS: Limited sample size and risk of false-positive findings. DISCUSSION: Our data suggest a possible role of these 3 genes in BPD. Alterations of 1 or more common brain pathways (e.g., neurodevelopment and neuroplasticity, calcium signaling) may explain the obtained results.

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.

Genetics of psychotropic medication induced side effects in two independent samples of bipolar patients.

The treatment of bipolar disorder (BD) usually requires combination therapies, with the critical issue of the emergence of adverse drug reactions (ADRs) and the possibility of low treatment adherence. Genetic polymorphisms are hypothesized to modulate the pharmacodynamics of psychotropic drugs, representing potential biological markers of ADRs. This study investigated genes involved in the regulation of neuroplasticity (BDNF, ST8SIA2), second messenger cascades (GSK3B, MAPK1, and CREB1), circadian rhythms (RORA), transcription (SP4, ZNF804A), and monoaminergic system (HTR2A and COMT) in the risk of neurological, psychic, autonomic, and other ADRs. Two independent samples of BD patients naturalistically treated were included (COPE-BD n = 147; STEP-BD n = 659). In the COPE-BD 34 SNPs were genotyped, while in the STEP-BD polymorphisms in the selected genes were extracted from the genome-wide dataset. Each ADRs group was categorized as absent-mild or moderate-severe and logistic regression with appropriate covariates was applied to identify possible risk genotypes/alleles. 58.5 and 93.5 % of patients were treated with mood stabilizers, 44.2 and 50.7 % were treated with antipsychotics, and 69.4 and 46.1 % were treated with antidepressants in the COPE-BD and STEP-BD, respectively. Our findings suggested that ST8SIA2 may be associated with psychic ADRs, as shown in the COPE-BD (rs4777989 p = 0.0017) and STEP-BD (rs56027313, rs13379489 and rs10852173). A cluster of RORA SNPs around rs2083074 showed an effect on psychic ADRs in the STEP-BD. Trends supporting the association between HTR2A and autonomic ADRs were found in both samples. Confirmations are needed particularly for ST8SIA2 and RORA since the few available data regarding their role in relation to psychotropic ADRs.

Failure to replicate influence of GRIK4 and GNB3 polymorphisms on treatment outcome in major depression.

In the present study, we aimed to confirm the previous finding of an association between GRIK4 and GNB3 variants (rs195478 and rs5443) and remission and treatment resistance in major depression, using a multicenter sample of 223 patients. We did not find any supporting evidence for such associations. These conflicting data may result from difficulties in the replication of candidate gene association studies.

Case-control association study for 10 genes in patients with schizophrenia: influence of 5HTR1A variation rs10042486 on schizophrenia and response to antipsychotics.

The aim of this study is to investigate possible associations between a set of single-nucleotide polymorphisms (SNPs) within 10 genes with Schizophrenia (SCZ) and response to antipsychotics in Korean in-patients treated with antipsychotics. Two hundred and twenty-one SCZ in-patients and 170 psychiatrically healthy controls were genotyped for 42 SNPs within ABCB1, ABCB4, TAP2, CLOCK, CPLX1, CPLX2, SYN2, NRG1, 5HTR1A and GPRIN2. Baseline and final clinical measures, including the Positive and Negative Symptoms Scale (PANSS), were recorded. Rs10042486 within 5HTR1A was associated with both SCZ and clinical improvement on PANSS total scores as well as on PANSS positive and PANSS negative scores. The haplotype analyses focusing on the four, three and two blocks' haplotypes within 5HTR1A confirmed such findings as well. We did not observe any significant association between the remaining genetic variants under investigation in this study and clinical outcomes. Our preliminary findings suggest that rs10042486 within 5HTR1A promoter region could be associated with SCZ and with clinical improvement on PANSS total, positive and negative scores in Korean patients with SCZ. However, taking into account the several limitations of our study, further research is needed to draw more definitive conclusions.

Influence of GRIA1, GRIA2 and GRIA4 polymorphisms on diagnosis and response to treatment in patients with major depressive disorder.

The present study is aimed to exploring whether some single nucleotide polymorphisms (SNPs) within GRIA1, GRIA2 and GRIA4 could be associated with major depressive disorder (MDD) and whether they could predict clinical outcomes in Korean in-patients, respectively, treated with antidepressants. One hundred forty-five (145) patients with MDD and 170 healthy controls were genotyped for 17 SNPs within GRIA1, GRIA2 and GRIA4. Baseline and final clinical measures, including the Montgomery-Asberg Depression Rating Scale (MADRS) for patients with MDD, were recorded. No association was observed between alleles, genotypes and haplotypes under investigation and clinical and demographical variables. As a secondary finding, a marginal association was observed between rs4302506 and rs4403097 alleles within GRIA2 and age of onset in patients with MDD. Our findings provide evidence for a possible association between rs4302506 and rs4403097 SNPs and age of onset in patients with MDD. However, taking into account that the several limitations of our study including the moderately small sample size of our study, our findings should be considered with caution and further research is needed to draw more definitive conclusions.

Case-control association study of GRIA1, GRIA2 and GRIA4 polymorphisms in bipolar disorder.

OBJECTIVE: The present study aimed to investigate whether some single nucleotide polymorphisms (SNPs) within GRIA1, GRIA2 and GRIA4 could be associated with bipolar disorder (BD) and they could predict clinical outcomes in in-patients with BD treated with mood stabilizers. METHODS: One hundred and thirty-two (132) patients with BD and 170 healthy controls were genotyped for 17 SNPs within GRIA1, GRIA2 and GRIA4. Baseline and final clinical measures including Young Mania Rating Scale for patients with BD were recorded. Statistical significance was set at the 0.005 level in order to reduce the likelihood of false positive results. RESULTS: We failed to show an evidence for a possible association of GRIA1, GRIA2 and GRIA4 with BD patients, in terms of influences on diagnosis and treatment outcomes, although this was the first study to explore the influence of such genes for bipolar disorder. CONCLUSION: Our results suggest that 17 SNPs within GRIA1, GRIA2 and GRIA4 may not be associated with the development and treatment outcomes in BD. However, taking into account that the several limitations of our study including the moderately small sample size of our study, our findings should be considered with caution and further research is needed to draw more definitive conclusions.

Metabolizing status of CYP2C19 in response and side effects to medications for depression: Results from a naturalistic study.

Major depressive disorder (MDD) is one of the leading causes of disability worldwide. Polymorphisms in cytochrome P450 genes (CYP450) were demonstrated to play a significant role in antidepressant response and side effects, but their effect in real-world clinical practice is poorly known. We determined the metabolic status of CYP2C19 based on the combination of *1, *2, *3 and *17 alleles extracted from genome-wide data in 1239 patients with MDD, pharmacologically treated in a naturalistic setting. Symptom improvement and side effects were assessed using the Montgomery and Åsberg Depression Rating Scale and the Udvalg for Kliniske Undersøgelse scale, respectively. We tested if symptom improvement, response and side effects were associated with CYP2C19 metabolic status adjusting for potential confounders. We considered patients treated with drugs for depression having CYP2C19 genotyping recommended by guidelines (T1 Drugs); secondarily, with all psychotropic drugs having CYP2C19 as relevant metabolic path (T2 Drugs). In the group treated with T1 drugs (n = 540), poor metabolizers (PMs) showed higher response and higher symptom improvement compared to normal metabolizers (p = 0.023 and p = 0.009, respectively), but also higher risk of autonomic and neurological side effects (p = 0.022 and p = 0.022 respectively). In patients treated with T2 drugs (n = 801), similar results were found. No associations between metabolizer status and other types of side effects were found (psychic and other side effects). Our study suggests potential advantages of CYP2C19 pharmacogenetic testing to guide treatment prescription, that may not be limited to the drugs currently recommended by guidelines.

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.