Psychiatric disorders and related traits have a demonstrated genetic component, with heritability estimated by twin studies generally between 80% and 40%. Their pathogenesis is complex and ...multi‐determined: environmental factors interact with a polygenic architecture, making difficult the development of models able to stratify patients or predict mental health outcomes. Despite this difficult challenge, relevant progress has been made in the field of psychiatric genetics in recent years. This review aims to present the main current methods in psychiatric genetics, their output, limitations, clinical applications, and possible future developments. Genome‐wide association studies (GWASs) performed in increasingly large samples have led to the identification of replicated genetic loci associated with the risk of major psychiatric disorders, including schizophrenia and mood disorders. Statistical and biological approaches have been developed to improve our understanding of the etiopathogenetic mechanisms behind genome‐wide significant associations, as well as for estimating the cumulative effect of risk variants at the individual level and the genetic overlap between different disorders, as pleiotropy is the rule rather than the exception. Clinical applications are available in the pharmacogenetics field. The main issues that remain to be addressed include improving ethnic diversity in genetic studies and the optimization of statistical power through methodological improvements, such as the definition of dimensional phenotypes with specific biological correlates and the integration of different types of omics data.
The microbiome of the oral cavity is the second-largest and diverse microbiota after the gut, harboring over 700 species of bacteria and including also fungi, viruses, and protozoa. With its diverse ...niches, the oral cavity is a very complex environment, where different microbes preferentially colonize different habitats. Recent data indicate that the oral microbiome has essential functions in maintaining oral and systemic health, and the emergence of 16S rRNA gene next-generation sequencing (NGS) has greatly contributed to revealing the complexity of its bacterial component. However, a detailed site-specific map of oral microorganisms (including also eukaryotes and viruses) and their relative abundance is still missing. Here, we aimed to obtain a comprehensive view of the healthy oral microbiome (HOM), including its drug-resistance features.
The oral microbiome of twenty healthy subjects was analyzed by whole-genome sequencing (WGS) and real-time quantitative PCR microarray. Sampled oral micro-habitat included tongue dorsum, hard palate, buccal mucosa, keratinized gingiva, supragingival and subgingival plaque, and saliva with or without rinsing. Each sampled oral niche evidenced a different microbial community, including bacteria, fungi, and viruses. Alpha-diversity evidenced significant differences among the different sampled sites (p < 0.0001) but not among the enrolled subjects (p = 0.876), strengthening the notion of a recognizable HOM. Of note, oral rinse microbiome was more representative of the whole site-specific microbiomes, compared with that of saliva. Interestingly, HOM resistome included highly prevalent genes conferring resistance to macrolide, lincosamides, streptogramin, and tetracycline.
The data obtained in 20 subjects by WGS and microarray analysis provide for the first time a comprehensive view of HOM and its resistome, contributing to a deeper understanding of the composition of oral microbiome in the healthy subject, and providing an important reference for future studies, allowing to identify microbial signatures related to functional and metabolic alterations associated with diseases, potentially useful for targeted therapies and precision medicine.
The pharmacogenetics of antidepressants has been not only a challenging but also frustrating research field since its birth in the 1990s. Indeed, great expectations followed the first evidence of ...familiar aggregation of antidepressant response. Despite the progress from candidate gene studies to genome-wide association studies (GWAS), results fell out the expectations and they were often inconsistent. Anyway, the cumulative evidence supports the involvement of some genes and molecular pathways in antidepressant efficacy. The best single genes are
SLC6A4
,
HTR2A
,
BDNF
,
GNB3
,
FKBP5
,
ABCB1
, and cytochrome P450 genes (
CYP2D6
and
CYP2C19
). Molecular pathways involved in inflammation and neuroplasticity show the greatest support. The first studies evaluating benefits of genotype-guided antidepressant treatments provided encouraging results and confirmed the relevance of
SLC6A4
,
HTR2A
,
ABCB1
, and cytochrome P450 genes. Further progress in genotyping and data analysis would allow to move forward and complete the understanding of antidepressant pharmacogenetics and its translation into clinical applications.
Treatment-resistant depression (TRD) is a major contributor to the disability caused by major depressive disorder (MDD). Primary care electronic health records provide an easily accessible approach ...to investigate TRD clinical and genetic characteristics. MDD defined from primary care records in UK Biobank (UKB) and EXCEED studies was compared with other measures of depression and tested for association with MDD polygenic risk score (PRS). Using prescribing records, TRD was defined from at least two switches between antidepressant drugs, each prescribed for at least 6 weeks. Clinical-demographic characteristics, SNP-based heritability (h
) and genetic overlap with psychiatric and non-psychiatric traits were compared in TRD and non-TRD MDD cases. In 230,096 and 8926 UKB and EXCEED participants with primary care data, respectively, the prevalence of MDD was 8.7% and 14.2%, of which 13.2% and 13.5% was TRD, respectively. In both cohorts, MDD defined from primary care records was strongly associated with MDD PRS, and in UKB it showed overlap of 71-88% with other MDD definitions. In UKB, TRD vs healthy controls and non-TRD vs healthy controls h
was comparable (0.25 SE = 0.04 and 0.19 SE = 0.02, respectively). TRD vs non-TRD was positively associated with the PRS of attention deficit hyperactivity disorder, with lower socio-economic status, obesity, higher neuroticism and other unfavourable clinical characteristics. This study demonstrated that MDD and TRD can be reliably defined using primary care records and provides the first large scale population assessment of the genetic, clinical and demographic characteristics of TRD.
Bipolar disorder (BD) shows one of the strongest genetic predispositions among psychiatric disorders and the identification of reliable genetic predictors of treatment response could significantly ...improve the prognosis of the disease.
The present study investigated genetic predictors of long-term treatment–outcome in 723 patients with BD type I from the STEP-BD (Systematic Treatment Enhancement Program for Bipolar Disorder) genome-wide dataset. BD I patients with >6months of follow-up and without any treatment restriction (reflecting a natural setting scenario) were included. Phenotypes were the total and depressive episode rates and the occurrence of one or more (hypo)manic/mixed episodes during follow-up. Quality control of genome-wide data was performed according to standard criteria and linear/logistic regression models were used as appropriate under an additive hypothesis. Top genes were further analyzed through a pathway analysis.
Genes previously involved in the susceptibility to BD (DFNB31, SORCS2, NRXN1, CNTNAP2, GRIN2A, GRM4, GRIN2B), antidepressant action (DEPTOR, CHRNA7, NRXN1), and mood stabilizer or antipsychotic action (NTRK2, CHRNA7, NRXN1) may affect long-term treatment outcome of BD. Promising findings without previous strong evidence were TRAF3IP2-AS1, NFYC, RNLS, KCNJ2, RASGRF1, NTF3 genes. Pathway analysis supported particularly the involvement of molecules mediating the positive regulation of MAPK cascade and learning/memory processes.
Further studies focused on the outlined genes may be helpful to provide validated markers of BD treatment outcome.
•Genetic markers of long-term treatment outcome could improve the prognosis of bipolar disorder.•Single SNPs and molecular pathways were analyzed in a genome-wide association study.•TRAF3IP2-AS1, RNLS, DFNB31, NFYC and DEPTOR genes were predictors of total episode rate.•The DFNB31 gene was strongly associated with the risk of depressive recurrence.•Top pathways mediate the regulation of MAPK cascade and learning/memory processes.
The empirical approach to drug choice and dosing in depression often results into inadequate response and side effects. Pharmacogenetic (PGx) testing appears a promising way to implement personalized ...treatments.
A systematic review was performed to identify available PGx tests, compare the genes they include with clinical guidelines and drug labels, and assess the quality of published clinical studies.
~40 commercial PGx tests are available and potential benefits were estimated for nine of them by clinical studies. The most part of studies are observational (9/21) or non-randomized case-control trials that compared standard care with PGx-guided treatment (6/21), six randomized controlled trials (RCTs) are available. The only genes included in all the available PGx tests and with recommendations in current clinical guidelines and drug labels are CYP2D6 and CYP2C19. There is heterogeneity among outcome measures across studies (response, remission, improvement, health care utilization, medication tolerability), as well as in trial design. Relatively weak clinical benefits were reported by RCTs and higher clinical benefits by non-RCTs, but the last group showed greater risk of bias. Lack of patient and rater's blindness, retrospective design and possible confounders (concomitant medications and medical diseases, lack of wash out prior to inclusion, no assessment of compliance etc.) were the main issues. Estimations of cost savings provided heterogeneous findings.
Variants in CYP2D6 and CYP2C19 have already adequate support for clinical application. The development of future PGx tests should include best practices for clinical evidence development and for health economic assessment.
•Pharmacogenetic (PGx) testing may provide personalized treatments for depression.•Dozens of PGx testing kits are commercialized and they include different variant panels.•Effectiveness and particularly cost/utility of PGx testing are still unclear.•The highest level of evidence was provided for CYP2C19 and CYP2D6 genes.•Best practices for experimental evidence development and economic assessment should be applied.
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 pharmacodynamic genes. We discuss possible reasons for these inconsistent findings and propose new study designs.
Second generation antipsychotics (SGAs) are effective options in the treatment of schizophrenia and mood disorders, each with characteristic efficacy and safety features. In order to optimize the ...balance between efficacy and side effects, it is of upmost importance to match compound specificity against patient clinical profile. As the number of SGAs increased, this review can assist physicians in the prescription of three novel SGAs already on the market, namely lurasidone, brexpiprazole, cariprazine, and lumateperone, which is in the approval phase for schizophrenia treatment at the FDA.
Besides schizophrenia, EMA and/or FDA approved lurasidone for bipolar depression, brexpiprazole as augmentation in major depressive disorder and cariprazine for the acute treatment of manic or mixed episodes associated with bipolar I disorder. These new antipsychotics were developed with the aim of improving efficacy on negative and depressive symptoms and reducing metabolic and cardiovascular side effects compared to prior SGAs, while keeping the risk of extrapyramidal symptoms low. They succeeded quite well in containing these side effects, despite weight gain during acute treatment remains a possible concern for brexpiprazole, while cariprazine and lurasidone show higher risk of akathisia compared to placebo and other SGAs such as olanzapine. The available studies support the expected benefits on negative symptoms, cognitive dysfunction and depressive symptoms, while the overall effect on acute psychotic symptoms may be similar to other SGAs such as quetiapine, aripiprazole and ziprasidone.
The discussed new antipsychotics represent useful therapeutic options but their efficacy and side effect profiles should be considered to personalize prescription.
Major depressive disorder (MDD) is the single largest contributor to global disability and up to 20-30% of patients do not respond to at least two antidepressants (treatment-resistant depression, ...TRD). This study leveraged imputed gene expression in TRD to perform a drug repurposing analysis. Among those with MDD, we defined TRD as having at least two antidepressant switches according to primary care records in UK Biobank (UKB). We performed a transcriptome-wide association study (TWAS) of TRD (n = 2165) vs healthy controls (n = 11,188) using FUSION and gene expression levels from 21 tissues. We identified compounds with opposite gene expression signatures (ConnectivityMap data) compared to our TWAS results using the Kolmogorov-Smirnov test, Spearman and Pearson correlation. As symptom patterns are routinely assessed in clinical practice and could be used to provide targeted treatments, we identified MDD subtypes associated with TRD in UKB and analysed them using the same pipeline described for TRD. Anxious MDD (n = 14,954) and MDD with weight gain (n = 4697) were associated with TRD. In the TWAS, two genes were significantly dysregulated (TMEM106B and ATP2A1 for anxious and weight gain MDD, respectively). A muscarinic receptor antagonist was identified as top candidate for repurposing in TRD; inhibition of heat shock protein 90 was the main mechanism of action identified for anxious MDD, while modulators of metabolism such as troglitazone showed promising results for MDD with weight gain. This was the first TWAS of TRD and associated MDD subtypes. Our results shed light on possible pharmacological approaches in individuals with difficult-to-treat depression.
Resilience is the ability to cope with critical situations through the use of personal and socially mediated resources. Since a lack of resilience increases the risk of developing stress‐related ...psychiatric disorders such as posttraumatic stress disorder (PTSD) and major depressive disorder (MDD), a better understanding of the biological background is of great value to provide better prevention and treatment options. Resilience is undeniably influenced by genetic factors, but very little is known about the exact underlying mechanisms. A recently published genome‐wide association study (GWAS) on resilience has identified three new susceptibility loci, DCLK2, KLHL36, and SLC15A5. Further interesting results can be found in association analyses of gene variants of the stress response system, which is closely related to resilience, and PTSD and MDD. Several promising genes, such as the COMT (catechol‐O‐methyltransferase) gene, the serotonin transporter gene (SLC6A4), and neuropeptide Y (NPY) suggest gene × environment interaction between genetic variants, childhood adversity, and the occurrence of PTSD and MDD, indicating an impact of these genes on resilience. GWAS on PTSD and MDD provide another approach to identifying new disease‐associated loci and, although the functional significance for disease development for most of these risk genes is still unknown, they are potential candidates due to the overlap of stress‐related psychiatric disorders and resilience. In the future, it will be important for genetic studies to focus more on resilience than on pathological phenotypes, to develop reasonable concepts for measuring resilience, and to establish international cooperations to generate sufficiently large samples.
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