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Identifying phenotypes at high risk of suicidal behaviour is a relevant objective of clinical and translational research and can facilitate the identification of possible candidate biomarkers. We probed the potential association and eventual stability of neuropsychological profiles and serum BDNF concentrations with lifetime suicide ideation and attempts (LSI and LSA, respectively) in individuals with schizophrenia (SCZ) and schizoaffective disorder (SCA) in a 2-year follow-up study. A secondary analysis was conducted on a convenience sample of previously recruited subjects from a single outpatient clinic. Retrospectively assessed LSI and LSA were recorded by analysing the available longitudinal clinical health records. LSI + LSA subjects consistently exhibited lower PANSS-defined negative symptoms and better performance in the BACS-letter fluency subtask. There was no significant association between BDNF levels and either LSI or LSA. We found a relatively stable pattern of lower negative symptoms over two years among patients with LSI and LSA. No significant difference in serum BDNF concentrations was detected. The translational viability of using neuropsychological profiles as a possible avenue for the identification of populations at risk for suicide behaviours rather than the categorical diagnosis represents a promising option but requires further confirmation.
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Fator Neurotrófico Derivado do Encéfalo , Cognição , Transtornos Psicóticos , Humanos , Fator Neurotrófico Derivado do Encéfalo/sangue , Masculino , Transtornos Psicóticos/sangue , Transtornos Psicóticos/psicologia , Transtornos Psicóticos/metabolismo , Feminino , Adulto , Estudos Longitudinais , Pessoa de Meia-Idade , Ideação Suicida , Esquizofrenia/sangue , Esquizofrenia/metabolismo , Tentativa de Suicídio/psicologia , Suicídio/psicologia , Biomarcadores/sangue , PsicopatologiaRESUMO
BACKGROUND: It has been suggested that bipolar disorder (BD) is associated with clinical and biological features of accelerated aging. In our previous studies, we showed that long-term lithium treatment was correlated with longer leukocyte telomere length (LTL) in BD patients. A recent study explored the role of TL in BD using patients-derived lymphoblastoid cell lines (LCLs), showing that baseline TL was shorter in BD compared to controls and that lithium in vitro increased TL but only in BD. Here, we used the same cell system (LCLs) to explore if a 7-day treatment protocol with lithium chloride (LiCl) 1 mM was able to highlight differences in TL between BD patients clinically responders (Li-R; n = 15) or non-responders (Li-NR; n = 15) to lithium, and if BD differed from non-psychiatric controls (HC; n = 15). RESULTS: There was no difference in TL between BD patients and HC. Moreover, LiCl did not influence TL in the overall sample, and there was no difference between diagnostic or clinical response groups. Likewise, LiCl did not affect TL in neural precursor cells from healthy donors. CONCLUSIONS: Our findings suggest that a 7-day lithium treatment protocol and the use of LCLs might not represent a suitable approach to deepen our understanding on the role of altered telomere dynamics in BD as previously suggested by studies in vivo.
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Transtorno Bipolar , Células-Tronco Neurais , Transtorno Bipolar/diagnóstico , Transtorno Bipolar/tratamento farmacológico , Transtorno Bipolar/genética , Linhagem Celular , Humanos , Lítio/farmacologia , Lítio/uso terapêutico , Cloreto de Lítio/farmacologia , Cloreto de Lítio/uso terapêutico , Compostos de Lítio/farmacologia , Compostos de Lítio/uso terapêutico , Células-Tronco Neurais/metabolismo , Telômero/genéticaRESUMO
Excessive predominance of pathological species in the gut microbiota could increase the production of inflammatory mediators at the gut level and, via modification of the gut-blood barrier, at the systemic level. This pro-inflammatory state could, in turn, increase biological aging that is generally proxied by telomere shortening. In this study, we present findings from a secondary interaction analysis of gut microbiota, aging, and inflammatory marker data from a cohort of patients with different diagnoses of severe mental disorders. We analyzed 15 controls, 35 patients with schizophrenia (SCZ), and 31 patients with major depressive disorder (MDD) recruited among those attending a community mental health center (50 males and 31 females, mean and median age 46.8 and 46.3 years, respectively). We performed 16S rRNA sequencing as well as measurement of telomere length via quantitative fluorescence in situ hybridization and high-sensitivity C-reactive protein. We applied statistical modeling with logistic regression to test for interaction between gut microbiota and these markers. Our results showed statistically significant interactions between telomere length and gut microbiota pointing to the genus Lachnostridium, which remained significantly associated with a reduced likelihood of MDD even after adjustment for a series of covariates. Although exploratory, these findings show that specific gut microbiota signatures overexpressing Lachnoclostridium and interacting with biological aging could modulate the liability for MDD.
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Transtorno Depressivo Maior , Microbioma Gastrointestinal , Masculino , Feminino , Humanos , Microbioma Gastrointestinal/genética , Transtorno Depressivo Maior/metabolismo , RNA Ribossômico 16S/genética , RNA Ribossômico 16S/análise , Hibridização in Situ Fluorescente , Envelhecimento/genética , ClostridialesRESUMO
Major depressive disorder (MDD) is a chronic, severe psychiatric illness with an incidence of 3% worldwide. MDD patients have a significantly impaired quality of life and reduced life expectancy compared to unaffected individuals, the latter being largely accounted for by an increased incidence of suicide and cardiovascular disorders. The premature mortality observed in MDD has been considered a signature of accelerated aging, a hypothesis supported by data showing altered functioning and morphology of several brain regions that are typically present in the aging population. Telomere shortening is a hallmark of cellular aging, and as such several studies explored the involvement of disrupted telomere dynamics in MDD, reporting contrasting findings. In the current study, we measured leukocyte telomere length (LTL) in a sample of 54 MDD patients and 47 non-psychiatric controls characterized for response to antidepressant treatment. After correcting for age, sex, and body mass index, we showed significantly reduced LTL in affected individuals compared to controls (beta = -.22, p = .02). There was no difference in LTL between treatment resistant or responsive MDD patients. Moreover, we observed no correlation between lifetime exposure to antidepressants and LTL. Our study showed that MDD patients have shorter telomeres compared to controls, supporting the hypothesis of accelerated aging in this disorder. However, LTL seemed not to be influenced by antidepressant treatment or to correlate with clinical response to these antidepressants. Further investigations in larger samples and possibly with longitudinal design are warranted to elucidate the role of altered telomere dynamics in MDD.
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Antidepressivos/administração & dosagem , Transtorno Depressivo Maior/fisiopatologia , Encurtamento do Telômero/fisiologia , Telômero/fisiologia , Adulto , Idoso , Envelhecimento/fisiologia , Estudos de Casos e Controles , Transtorno Depressivo Maior/tratamento farmacológico , Transtorno Depressivo Resistente a Tratamento/tratamento farmacológico , Transtorno Depressivo Resistente a Tratamento/fisiopatologia , Feminino , Humanos , Leucócitos/fisiologia , Masculino , Pessoa de Meia-IdadeRESUMO
Lithium is the mainstay in the maintenance of bipolar disorder (BD) and the most efficacious pharmacological treatment in suicide prevention. Nevertheless, its use is hampered by a high interindividual variability and important side effects. Genetic and epigenetic factors have been suggested to modulate lithium response, but findings so far have not allowed identifying molecular targets with predictive value. In this study we used next generation sequencing to measure genome-wide miRNA expression in lymphoblastoid cell lines from BD patients excellent responders (ER, n = 12) and non-responders (NR, n = 12) to lithium. These data were integrated with microarray genome-wide expression data to identify pairs of miRNA/mRNA inversely and significantly correlated. Significant pairs were prioritized based on strength of association and in-silico miRNA target prediction analyses to select candidates for validation with qRT-PCR. Thirty-one miRNAs were differentially expressed in ER vs. NR and inversely correlated with 418 genes differentially expressed between the two groups. A total of 331 of these correlations were also predicted by in-silico algorithms. miR-320a and miR-155-3p, as well as three of their targeted genes (CAPNS1 (Calpain Small Subunit 1) and RGS16 (Regulator of G Protein Signaling 16) for miR-320, SP4 (Sp4 Transcription Factor) for miR-155-3p) were validated. These miRNAs and mRNAs were previously implicated in psychiatric disorders (miR-320a and SP4), key processes of the central nervous system (CAPNS1, RGS16, SP4) or pathways involved in mental illnesses (miR-155-3p). Using an integrated approach, we identified miRNAs and their targeted genes potentially involved in lithium response in BD.
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Transtorno Bipolar/tratamento farmacológico , Lítio/uso terapêutico , MicroRNAs/genética , Psicotrópicos/uso terapêutico , RNA Mensageiro/genética , Adulto , Transtorno Bipolar/genética , Transtorno Bipolar/metabolismo , Transtorno Bipolar/fisiopatologia , Calpaína/genética , Calpaína/metabolismo , Linhagem Celular , Feminino , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Genoma Humano , Humanos , Linfócitos/efeitos dos fármacos , Linfócitos/metabolismo , Linfócitos/patologia , Masculino , MicroRNAs/classificação , MicroRNAs/metabolismo , Pessoa de Meia-Idade , Análise de Sequência com Séries de Oligonucleotídeos , Cultura Primária de Células , Proteínas RGS/genética , Proteínas RGS/metabolismo , RNA Mensageiro/classificação , RNA Mensageiro/metabolismo , Estudos Retrospectivos , Fator de Transcrição Sp4/genética , Fator de Transcrição Sp4/metabolismo , Resultado do TratamentoRESUMO
Lithium is the mainstay treatment in bipolar disorder (BD) for its effectiveness in the acute phases of illness and in prevention of recurrences. Lithium's mechanism of action is complex, and while it modulates the function of hundreds of molecular targets, most of these effects could be unspecific and not relevant for its clinical efficacy. In this study, we applied an integrated analytical approach using genome-wide expression and genotyping data from BD patients to identify lithium-responsive genes that may serve as biomarkers of its efficacy. To this purpose, we tested the effect of treatment with lithium chloride 1 mM on the transcriptome of lymphoblasts from 10 lithium responders (LR) and 10 nonresponders (NR) patients and identified genes significantly influenced by the treatment exclusively in LR. These findings were integrated with gene-based analysis on genome-wide genotyping data from an extended sample of 205 BD patients characterized for lithium response. The expression of 29 genes was significantly changed by lithium exclusively in LR. Gene-based analysis showed that two of these genes, zinc finger protein 429 (ZNF429) and zinc finger protein 493 (ZNF493), were also significantly associated with lithium response. Validation with quantitative real-time polymerase chain reaction confirmed the lithium-induced downregulation of ZNF493 in LR (p = .036). Using convergent analyses of genome-wide expression and genotyping data, we identified ZNF493 as a potential lithium-responsive target that may be involved in modulating lithium efficacy in BD. To our knowledge, this is the first evidence supporting the involvement of zinc finger proteins in lithium response.
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Transtorno Bipolar/genética , Lítio/metabolismo , Lítio/farmacologia , Biomarcadores Farmacológicos , Biologia Computacional/métodos , Proteínas de Ligação a DNA/genética , Feminino , Perfilação da Expressão Gênica/métodos , Estudo de Associação Genômica Ampla/métodos , Genótipo , Humanos , Masculino , Análise de Sequência com Séries de Oligonucleotídeos/métodos , Estudos Retrospectivos , Fatores de Transcrição/genética , Transcriptoma , Resultado do Tratamento , Dedos de Zinco/genéticaRESUMO
BACKGROUND: Medication overuse headache (MOH) is a common and debilitating disorder characterized by generation, perpetuation, and persistence of intense chronic migraine, caused by overuse of analgesics, triptans, or other acute headache compounds. It has been suggested that MOH could share some pathogenetic mechanisms with other kinds of drug addiction. In this regard, histone deacetylases 3 (HDAC3) seems to have a role in the memory processes involved in extinction of drug-seeking behavior in animal models. HDAC3 is inhibited by sodium valproate, a drug with proven efficacy in MOH. Recent evidence suggests an involvement of genetic factors in predisposition to medication overuse. RESULTS: In this association study, we sequenced all exons, intron/exon junctions, and 3'-5'UTR regions of HDAC3 in 23 MOH patients to investigate its role in medication overuse. Associations between genotypes with continuous and dichotomous clinical characteristics were tested by multivariate analysis and Fisher's exact test, respectively. Sequencing of HDAC3 revealed six single-nucleotide polymorphisms. The G allele of rs2530223 was significantly associated with the number of acute medications/month used and with the number of days/month in which medications were used (p = 0.006 and p = 0.007, respectively), but neither with headache frequency or intensity. None of the single-nucleotide polymorphisms (SNPs) was associated with clinical characteristics or response to sodium valproate. CONCLUSIONS: HDAC3 could be implicated in excessive medication consumption in MOH patients. Our preliminary findings provide support for the need of further investigation on larger independent samples to confirm and extend the role of HDAC3 in medication overuse headache.
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Estudos de Associação Genética , Transtornos da Cefaleia Secundários/genética , Histona Desacetilases/genética , Transtornos de Enxaqueca/tratamento farmacológico , Adulto , Feminino , Transtornos da Cefaleia Secundários/induzido quimicamente , Transtornos da Cefaleia Secundários/patologia , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Pessoa de Meia-Idade , Transtornos de Enxaqueca/genética , Transtornos de Enxaqueca/patologia , Projetos Piloto , Polimorfismo de Nucleotídeo Único , Uso Excessivo de Medicamentos Prescritos , Ácido Valproico/efeitos adversosRESUMO
Patients with severe mental disorders such as bipolar disorder (BD), schizophrenia (SCZ) and major depressive disorder (MDD) show a substantial reduction in life expectancy, increased incidence of comorbid medical conditions commonly observed with advanced age and alterations of aging hallmarks. While severe mental disorders are heritable, the extent to which genetic predisposition might contribute to accelerated cellular aging is not known. We used bivariate causal mixture models to quantify the trait-specific and shared architecture of mental disorders and 2 aging hallmarks (leukocyte telomere length [LTL] and mitochondrial DNA copy number), and the conjunctional false discovery rate method to detect shared genetic loci. We integrated gene expression data from brain regions from GTEx and used different tools to functionally annotate identified loci and investigate their druggability. Aging hallmarks showed low polygenicity compared with severe mental disorders. We observed a significant negative global genetic correlation between MDD and LTL (rg = -0.14, p = 6.5E-10), and no significant results for other severe mental disorders or for mtDNA-cn. However, conditional QQ plots and bivariate causal mixture models pointed to significant pleiotropy among all severe mental disorders and aging hallmarks. We identified genetic variants significantly shared between LTL and BD (n = 17), SCZ (n = 55) or MDD (n = 19), or mtDNA-cn and BD (n = 4), SCZ (n = 12) or MDD (n = 1), with mixed direction of effects. The exonic rs7909129 variant in the SORCS3 gene, encoding a member of the retromer complex involved in protein trafficking and intracellular/intercellular signaling, was associated with shorter LTL and increased predisposition to all severe mental disorders. Genetic variants underlying risk of SCZ or MDD and shorter LTL modulate expression of several druggable genes in different brain regions. Genistein, a phytoestrogen with anti-inflammatory and antioxidant effects, was an upstream regulator of 2 genes modulated by variants associated with risk of MDD and shorter LTL. While our results suggest that shared heritability might play a limited role in contributing to accelerated cellular aging in severe mental disorders, we identified shared genetic determinants and prioritized different druggable targets and compounds.
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Senescência Celular , Transtorno Depressivo Maior , Pleiotropia Genética , Humanos , Senescência Celular/genética , Transtorno Depressivo Maior/genética , Transtorno Depressivo Maior/tratamento farmacológico , Transtorno Bipolar/genética , Transtornos Mentais/genética , Esquizofrenia/genética , DNA Mitocondrial/genética , Predisposição Genética para Doença/genética , Variações do Número de Cópias de DNA/genéticaRESUMO
Remission, relapse prevention, and clinical recovery are crucial areas of interest in schizophrenia (SCZ) research. Although SCZ is a chronic disorder with poor overall outcomes, years of research demonstrated that recovery is possible. There are considerable data linking brain-derived neurotrophic factor (BDNF) to SCZ, however, evidence on the role of BDNF in remission in SCZ is scarce. This secondary analysis of the Longitudinal Assessment of BDNF in Sardinian patients (LABSP) data aimed to investigate the relationship between serum BDNF levels and symptomatic remission, simultaneous clinical and functional remission, and recovery in patients with SCZ. A total of 105 patients with SCZ or schizoaffective disorder were recruited for a longitudinal assessment of BDNF levels over 24 months. Longitudinal data were analyzed using mixed-effects linear regression models. The study found significant associations between use of long acting injectables (χ2 = 7.075, df = 1, p = 0.008), baseline serum BDNF levels (U = 701, z = -2.543, p = 0.011), and "childhood" (U = 475, z = -2.124, p = 0.034) and "general" (U = 55, z = -2.014, p = 0.044) subscales of the Premorbid Adjustment Scale (PAS) with patients maintaining remission and recovery. The diagnosis of SCZ was significantly associated with lower BDNF levels for patients with simultaneous clinical and functional remission (Z = 2.035, p = 0.0419) and recovery (Z = 2.009, p = 0.0445) compared to those without. There were no significant associations between remission in the entire sample and longitudinal serum BDNF levels or genetic variants within the BDNF gene. These findings provide further insight into the complex relationship between BDNF and SCZ.
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Fator Neurotrófico Derivado do Encéfalo , Transtornos Psicóticos , Esquizofrenia , Humanos , Fator Neurotrófico Derivado do Encéfalo/genética , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Transtornos Psicóticos/genética , Transtornos Psicóticos/terapia , Esquizofrenia/genética , Esquizofrenia/terapia , Prevenção Secundária , Indução de RemissãoRESUMO
An altered polyamine system has been suggested to play a key role in mood disorders and suicide, a hypothesis corroborated by the evidence that lithium inhibits the polyamine mediated stress response in the rat brain. Recent post-mortem studies have shown that spermidine/spermine N1-acetyltransferase (SAT1), the key regulator of cellular polyamine content, is under-expressed in brains from suicide victims compared to controls. In our study we tested the effect of in vitro lithium treatment on SAT1 gene and protein expression in B lymphoblastoid cell lines (BLCLs) from bipolar disorder (BD) patients who committed suicide (and for which BLCLs were collected prior to their death), BD patients with high and low risk of suicide and a sample of non-psychiatric controls. Baseline mRNA levels were similar in the four groups of subjects (p > 0.05). Lithium had no effect in suicide completers (p > 0.05) while it significantly increased SAT1 expression in the high risk (p < 0.001) and low risk (p < 0.01) groups as well as in controls (p < 0.001). Protein and mRNA levels were not correlated; lithium significantly reduced protein levels only in the control sample (p < 0.05). Our findings suggest that SAT1 transcription is influenced by lithium and that this effect is altered in BD patients who completed suicide, further supporting a role for polyamines in suicide.
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Acetiltransferases/metabolismo , Antimaníacos/farmacologia , Linfócitos B/efeitos dos fármacos , Transtorno Bipolar/enzimologia , Transtorno Bipolar/psicologia , Cloreto de Lítio/farmacologia , Suicídio , Acetiltransferases/genética , Adulto , Linfócitos B/enzimologia , Transtorno Bipolar/sangue , Transtorno Bipolar/genética , Canadá , Estudos de Casos e Controles , Linhagem Celular , Feminino , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Humanos , Itália , Masculino , Pessoa de Meia-Idade , RNA Mensageiro/metabolismo , Ideação Suicida , Tentativa de Suicídio , Adulto JovemRESUMO
Bipolar disorder (BD) is a debilitating psychiatric disease characterized by alternating episodes of mania and depression. Among mood stabilizers, lithium is the mainstay for the treatment of BD, with approximately one-third of patients showing remission from episode recurrence. While there is evidence suggesting genetic load for lithium response in BD, its molecular underpinnings are still not completely understood. To identify genes potentially involved in (or correlated with) lithium response, we carried out a genome-wide expression analysis on lymphoblastoid cell lines (LCLs) from 10 BD patients responders (R) and 10 non-responders (NR) to lithium. We compared expression levels of the two groups and tested whether in vitro lithium treatment had different effects in LCLs of R compared to NR. At basal, 2060 genes were differentially expressed between R and NR while no genes were differentially regulated by lithium in the two groups. After pathway analysis based on the 2060 genes, 9 genes were selected for validation with qRT-PCR. Eight genes were validated in the same sample of LCLs while only insulin-like growth factor 1 (IGF-1) was significantly over-expressed in R compared to NR in the same sample as well as in an independent sample comprised of 6 R and 6 NR (sample 1, fold change=1.94; p=0.005; sample 2, fold change=2.21; p=0.005). IGF-1 was also significantly over-expressed in R but not in NR when compared to a sample of non-psychiatric controls. Our findings suggest that IGF-1 may be involved in lithium response, supporting further investigation on its potential as a biomarker.
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Antimaníacos/uso terapêutico , Transtorno Bipolar/genética , Fator de Crescimento Insulin-Like I/genética , Compostos de Lítio/uso terapêutico , Adulto , Transtorno Bipolar/tratamento farmacológico , Linhagem Celular , Feminino , Perfilação da Expressão Gênica , Estudo de Associação Genômica Ampla , Humanos , Linfócitos/citologia , Masculino , Pessoa de Meia-Idade , Análise de Sequência com Séries de Oligonucleotídeos , Regulação para CimaRESUMO
Background and Objectives: Alterations in hot cognition and in the tryptophan metabolism through serotonin (5-HT) and kynurenine (KYN) pathways have been associated with an increased risk of suicidal behavior. Here, we aim at probing the association between Stroop test performances and tryptophan pathway components in a sample of individuals with bipolar disorder (BD). Materials and Methods: We explored the association between the Emotion Inhibition Subtask (EIS) performances of the Brief Assessment of Cognition for Affective Disorders (BAC-A) and plasmatic levels of 5-hydroxytriptophan (5-HTP), 5-HT, KYN, 3-hydroxykynurenine (3-HK), quinolinic acid (QA), and kynurenic acid (KYNA) among subjects reporting lifetime suicide ideation (LSI) vs. non-LSI and subjects reporting lifetime suicide attempts (LSA) vs. non-LSA. Results: In a sample of 45 subjects with BD, we found a statistically significant different performance for LSA vs. non-LSA in the color naming (CN) and neutral words (NW) EIS subtasks. There was a significant association between CN performances and plasma 5-HTP levels among LSI and LSA subjects but not among non-LSI or non-LSA. Conclusions: In our sample, patients with LSA and LSI presented lower performances on some EIS subtasks compared to non-LSA and non-LSI. Moreover, we found an inverse correlation between plasma 5-HTP concentration and some EIS performances in LSA and LSI but not among non-LSA or non-LSI. This may represent an interesting avenue for future studies probing this complex association.
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The kynurenine pathway (KP) may play a role in the pathophysiology of bipolar disorder (BD). We conducted a genome-wide association study (GWAS) to identify genetic variants associated with the plasma levels of the metabolites of tryptophan (TRP) via the serotonin (5-HT) and kynurenine (KYN) pathways in 44 patients with BD and 45 healthy controls. We assessed whether variants that were differentially associated with metabolite levels based on the diagnostic status improved the prediction accuracy of BD using penalized regression approaches. We identified several genetic variants that were significantly associated with metabolites (5-HT, 5-hydroxytryptophan (5-HTP), TRP, and quinolinic acid (QA) or metabolite ratios (5-HTP/TRP and KYN/TRP) and for which the diagnostic status exerted a significant effect. The inclusion of genetic variants led to increased accuracy in the prediction of the BD diagnostic status. Specifically, we obtained an accuracy of 0.77 using Least Absolute Shrinkage and Selection Operator (LASSO) regression. The predictors retained as informative in this model included body mass index (BMI), the levels of TRP, QA, and 5-HT, the 5-HTP/TRP ratio, and genetic variants associated with the levels of QA (rs6827515, rs715692, rs425094, rs4645874, and rs77048355) and TRP (rs292212) or the 5-HTP/TRP ratio (rs7902231). In conclusion, our study identified statistically significant associations between metabolites of TRP via the 5-HT and KYN pathways and genetic variants at the genome-wide level. The discriminative performance of penalized regression models incorporating clinical, genetic, and metabolic predictors warrants a follow-up analysis of this panel of determinants.
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Brain-derived neurotrophic factor (BDNF) is a key modulator of neuroplasticity and has an important role in determining the susceptibility to severe psychiatric disorder with a significant neurodevelopmental component such as major psychoses. Indeed, a potential association between BDNF serum levels and schizophrenia (SCZ) and schizoaffective disorder (SAD) has been tested in diverse studies and a considerable amount of them found reduced BDNF levels in these disorders. Here, we aimed at testing the association of BDNF serum levels with several demographic, clinical, and psychometric measures in 105 patients with SCZ and SAD, assessing the moderating effect of genetic variants within the BDNF gene. We also verified whether peripheral BDNF levels differed between patients with SCZ and SAD. Our findings revealed that BDNF serum levels are significantly lower in patients affected by SCZ and SAD presenting more severe depressive symptomatology. This finding awaits replication in future independent studies and points to BDNF as a possible prognostic indicator in major psychoses.
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BACKGROUND AND HYPOTHESIS: Schizophrenia spectrum disorders are among the most debilitating mental disorders and has complex pathophysiological underpinnings. There is growing evidence that brain-derived neurotrophic factor (BDNF) can play a role in its pathogenesis. The present study investigated the longitudinal variation of serum BDNF levels in a 24-month observational prospective cohort study of Sardinian psychotic patients and its relationship with psychopathological and cognitive changes. Furthermore, we examined whether genetic variation within the BDNF gene could moderate these relationships. STUDY DESIGN: Every 6 months, 105 patients were assessed for their BDNF serum levels, as well as for a series of psychopathological, cognitive, and social measures. We performed a targeted analysis of four tag single nucleotide polymorphisms within the BDNF gene that were selected and analyzed using polymerase chain reaction. Longitudinal data were analyzed using mixed-effects linear regression models. STUDY RESULTS: We observed a declining longitudinal trajectory of BDNF levels in psychotic patients in general, and in relation to the severity of depressive and negative symptoms. BDNF serum levels also declined in patients scoring lower in cognitive measures such as attention and speed of information processing and verbal fluency. The rs7934165 polymorphism moderated the significant association between verbal fluency and BDNF levels. CONCLUSIONS: These findings in patients from real-world settings suggest a plausible role of peripheral BDNF levels as a marker of illness burden in schizophrenia spectrum disorders.
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Fator Neurotrófico Derivado do Encéfalo , Esquizofrenia , Humanos , Fator Neurotrófico Derivado do Encéfalo/genética , Estudos Prospectivos , Esquizofrenia/diagnóstico , Cognição/fisiologia , Polimorfismo de Nucleotídeo ÚnicoRESUMO
Bipolar disorder is associated with an inflammation-triggered elevated catabolism of tryptophan to the kynurenine pathway, which impacts psychiatric symptoms and outcomes. The data indicate that lithium exerts anti-inflammatory effects by inhibiting indoleamine-2,3-dioxygenase (IDO)-1 activity. This exploratory study aimed to investigate the tryptophan catabolism in individuals with bipolar disorder (n = 48) compared to healthy controls (n = 48), and the associations with the response to mood stabilizers such as lithium, valproate, or lamotrigine rated with the Retrospective Assessment of the Lithium Response Phenotype Scale (or the Alda scale). The results demonstrate an association of a poorer response to lithium with higher levels of kynurenine, kynurenine/tryptophan ratio as a proxy for IDO-1 activity, as well as quinolinic acid, which, overall, indicates a pro-inflammatory state with a higher degradation of tryptophan towards the neurotoxic branch. The treatment response to valproate and lamotrigine was not associated with the levels of the tryptophan metabolites. These findings support the anti-inflammatory properties of lithium. Furthermore, since quinolinic acid has neurotoxic features via the glutamatergic pathway, they also strengthen the assumption that the clinical drug response might be associated with biochemical processes. The relationship between the lithium response and the measurements of the tryptophan to the kynurenine pathway is of clinical relevance and may potentially bring advantages towards a personalized medicine approach to bipolar disorder that allows for the selection of the most effective mood-stabilizing drug.
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Patients with bipolar disorder (BD) often show increased risk-taking propensity, which may contribute to poor clinical outcome. While these two phenotypes are genetically correlated, there is scarce knowledge on the shared genetic determinants. Using GWAS datasets on BD (41,917 BD cases and 371,549 controls) and risk-taking (n = 466,571), we dissected shared genetic determinants using conjunctional false discovery rate (conjFDR) and local genetic covariance analysis. We investigated specificity of identified targets using GWAS datasets on schizophrenia (SCZ) and attention-deficit hyperactivity disorder (ADHD). The putative functional role of identified targets was evaluated using different tools and GTEx v. 8. Target druggability was evaluated using DGIdb and enrichment for drug targets with genome for REPositioning drugs (GREP). Among 102 loci shared between BD and risk-taking, 87% showed the same direction of effect. Sixty-two were specifically shared between risk-taking propensity and BD, while the others were also shared between risk-taking propensity and either SCZ or ADHD. By leveraging pleiotropic enrichment, we reported 15 novel and specific loci associated with BD and 22 with risk-taking. Among cross-disorder genes, CACNA1C (a known target of calcium channel blockers) was significantly associated with risk-taking propensity and both BD and SCZ using conjFDR (p = 0.001 for both) as well as local genetic covariance analysis, and predicted to be differentially expressed in the cerebellar hemisphere in an eQTL-informed gene-based analysis (BD, Z = 7.48, p = 3.8E-14; risk-taking: Z = 4.66, p = 1.6E-06). We reported for the first time shared genetic determinants between BD and risk-taking propensity. Further investigation into calcium channel blockers or development of innovative ligands of calcium channels might form the basis for innovative pharmacotherapy in patients with BD with increased risk-taking propensity.
Assuntos
Transtorno Bipolar , Transtorno Bipolar/tratamento farmacológico , Transtorno Bipolar/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Polimorfismo de Nucleotídeo Único/genética , Locos de Características Quantitativas , Assunção de RiscosRESUMO
The gut microbiota is constituted by more than 40,000 bacterial species involved in key processes including high order brain functions. Altered composition of gut microbiota has been implicated in psychiatric disorders and in modulating the efficacy and safety of psychotropic medications. In this work we characterized the composition of the gut microbiota in 38 patients with schizophrenia (SCZ) and 20 healthy controls (HC), and tested if SCZ patients with different response to antipsychotics (18 patients with treatment resistant schizophrenia (TRS), and 20 responders (R)) had specific patterns of gut microbiota composition associated with different response to antipsychotics. Moreover, we also tested if patients treated with typical antipsychotics (n = 20) presented significant differences when compared to patients treated with atypical antipsychotics (n = 31). Our findings showed the presence of distinct composition of gut microbiota in SCZ versus HC, with several bacteria at the different taxonomic levels only present in either one group or the other. Similar findings were observed also depending on treatment response and exposure to diverse classes of antipsychotics. Our results suggest that composition of gut microbiota could constitute a biosignatures of SCZ and TRS.
RESUMO
Psychiatric disorders seem to be characterized by premature cell senescence. However, controversial results have also been reported. In addition, the relationship between accelerated aging and treatment-resistance has scarcely been investigated. In the current study, we measured leukocyte telomere length (LTL) in 148 patients with treatment-resistant depression (TRD, 125 with major depressive disorder, MDD, and 23 with bipolar disorder, BD) treated with electroconvulsive therapy (ECT) and analyzed whether LTL was associated with different response profiles. We also compared LTL between patients with TRD and 335 non-psychiatric controls. For 107 patients for which genome-wide association data were available, we evaluated whether a significant overlap among genetic variants or genes associated with LTL and with response to ECT could be observed. LTL was negatively correlated with age (Spearman's correlation coefficient = -0.25, p < 0.0001) and significantly shorter in patients with treatment-resistant MDD (Quade's F = 35.18, p < 0.0001) or BD (Quade's F = 20.84, p < 0.0001) compared to controls. Conversely, baseline LTL was not associated with response to ECT or remission. We did not detect any significant overlap between genetic variants or genes associated with LTL and response to ECT. Our results support previous findings suggesting premature cell senescence in patients with severe psychiatric disorders and suggest that LTL could not be a predictive biomarker of response to ECT.
RESUMO
Post-mortem brain studies suggest that miRNAs may be involved in suicide, but their role as peripheral biomarkers or targets of preventive pharmacological treatments in suicide has yet to be elucidated. We used nCounter miRNA Expression assay to measure miRNAs expression in lymphoblastoid cell lines (LCLs) from patients with Bipolar Disorder (BD) who died by suicide (SC, n = 7) and with low risk of suicide (LR, n = 11). Five miRNAs were differentially expressed in SC compared to LR (false discovery rate p<0.05). The two most significant miRNAs were measured with RT-qPCR in the same sample and in 12 healthy controls (HC): miR-4286 was increased while miR-186-5p was decreased in SC compared to LR and HC (ANOVA F = 14.92, p = 0.000043 and F = 3.95, p = 0.032 respectively). miR-4286 was also decreased in postmortem brains from 12 patients with BD who died by suicide compared to 13 controls, even though it did not reach statistical significance (FC=0.51, p = 0.07). Treatment with lithium of human neural progenitor cells reduced the expression of miR-4286 (FC=0.30, p = 0.038). Pathway analysis on predicted miR-4286 targets showed that "insulin resistance" was significantly enriched after correction for multiple testing. This pathway comprised 17 genes involved in lipid and glucose metabolism, several of which were also dysregulated in postmortem brains from patients with BD who died by suicide from the Stanley-foundation array collection. In conclusion, our study suggests that miR-4286 could be a biomarker of suicide but further studies are warranted to investigate its targeted genes and how these could be involved in the neurobiology of suicide.