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2.
Brain Behav ; : e02075, 2021 Feb 18.
Artigo em Inglês | MEDLINE | ID: mdl-33599392

RESUMO

OBJECTIVE: Our previous metabolomics study showed that the plasma nervonic acid levels were higher in patients with major depressive disorder (MDD) than those in healthy controls and patients with bipolar disorder (BD). To examine whether the nervonic acid levels differ in the central nervous system, we investigated the levels in the cerebrospinal fluid (CSF) of patients with MDD, BD, and healthy controls. METHODS: Nervonic acid levels in CSF were measured by gas chromatography time-of-flight mass spectrometry. The participants included 30 patients with MDD, 30 patients with BD, and 30 healthy controls. RESULTS: In contrast to our previous study, no significant differences were found in the nervonic acid level in the CSF among the patients with MDD, BD, and the healthy controls. Though no significant state-dependent changes were found among the three groups, we did observe a significant negative correlation between the nervonic acid levels and depressive symptoms in the depressive state of patients with MDD and BD (r = -0.38, p = .046). Further, a significant positive correlation was found between the nervonic acid levels and manic symptoms in the manic state of patients with BD (r = 0.79, p = .031). CONCLUSION: The nervonic acid levels in the CSF did not differ among the patients with MDD, BD, and the healthy controls; however, a significant negative correlation with depressive symptoms and a positive correlation with manic symptoms was observed. Thus, the nervonic acid levels in the CSF may be a candidate biomarker for mood symptoms.

3.
Transl Psychiatry ; 11(1): 119, 2021 Feb 11.
Artigo em Inglês | MEDLINE | ID: mdl-33574244

RESUMO

SLC6A4, which encodes the serotonin transporter, has a functional polymorphism called the serotonin transporter-linked polymorphic region (5-HTTLPR). The 5-HTTLPR consists of short (S) and long (L) alleles, each of which has 14 or 16 tandem repeats. In addition, the extralong (XL) and other rare alleles have been reported in 5-HTTLPR. Although they are more frequent in Asian and African than in other populations, the extent of variations and allele frequencies (AFs) were not addressed in a large population. Here, we report the AFs of the rare alleles in a large number of Japanese subjects (N = 2894) consisting of two cohorts. The first cohort (case-control study set, CCSS) consisted of 1366 subjects, including 485 controls and 881 patients with psychosis (bipolar disorder or schizophrenia). The second cohort (the Arao cohort study set, ACSS) consisted of 1528 elderly subjects. During genotyping, we identified 11 novel 5-HTTLPR alleles, including 3 XL alleles. One novel allele had the longest subunit ever reported, consisting of 28 tandem repeats. We named this XL28-A. An in vitro luciferase assay revealed that XL28-A has no transcriptional activity. XL28-A was found in two unrelated patients with bipolar disorder in the CCSS and one healthy subject in the ACSS who did not show depressive symptoms or a decline in cognitive function. Therefore, it is unlikely that XL28-A is associated with psychiatric disorders, despite its apparent functional deficit. Our results suggest that unraveling the complex genetic variations of 5-HTTLPR will be important for further understanding its role in psychiatric disorders.

4.
Sci Rep ; 11(1): 1155, 2021 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-33441847

RESUMO

Predicting lithium response prior to treatment could both expedite therapy and avoid exposure to side effects. Since lithium responsiveness may be heritable, its predictability based on genomic data is of interest. We thus evaluate the degree to which lithium response can be predicted with a machine learning (ML) approach using genomic data. Using the largest existing genomic dataset in the lithium response literature (n = 2210 across 14 international sites; 29% responders), we evaluated the degree to which lithium response could be predicted based on 47,465 genotyped single nucleotide polymorphisms using a supervised ML approach. Under appropriate cross-validation procedures, lithium response could be predicted to above-chance levels in two constituent sites (Halifax, Cohen's kappa 0.15, 95% confidence interval, CI [0.07, 0.24]; and Würzburg, kappa 0.2 [0.1, 0.3]). Variants with shared importance in these models showed over-representation of postsynaptic membrane related genes. Lithium response was not predictable in the pooled dataset (kappa 0.02 [- 0.01, 0.04]), although non-trivial performance was achieved within a restricted dataset including only those patients followed prospectively (kappa 0.09 [0.04, 0.14]). Genomic classification of lithium response remains a promising but difficult task. Classification performance could potentially be improved by further harmonization of data collection procedures.

5.
J Affect Disord ; 281: 160-167, 2021 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-33321381

RESUMO

BACKGROUND: Lurasidone has demonstrated efficacy for short-term treatment of bipolar depression in a diverse ethnic population including Japanese. This study evaluated the long-term safety and effectiveness of open-label lurasidone treatment in these patients. METHODS: Patients for this 28-week extension study were recruited from those who completed a 6-week double-blind study of lurasidone, 20-60 mg/day, lurasidone 80-120 mg/day, and placebo. In the extension study, lurasidone was flexibly dosed (20 to 120 mg/day). Safety was evaluated in terms of change from extension-phase baseline to endpoint including adverse events, vital signs, body weight, ECG, laboratory tests, and measures of suicidality and extrapyramidal symptoms. Effectiveness was determined by Montgomery Åsberg Depression Rating Scale (MADRS) and other measures. RESULTS: 303 of 413 (73.3%) subjects completed the extension study. Discontinuation due to a treatment-emergent adverse event occurred for 11.4% of those who received placebo, and 8.9% of those who received lurasidone, in the prior 6-week trial. The most common treatment-emergent adverse event was akathisia. Minimal changes were evident on body weight and metabolic parameters. Long-term treatment with lurasidone further reduced mean MADRS total scores from long-term baseline to week 28 (or endpoint) for both those who had received prior placebo (-11.3), and those who had receive prior lurasidone (-8.9), in the 6-week double-blind trial. LIMITATIONS: There was no placebo control and treatment was not double-blind. CONCLUSIONS: Long-term treatment with lurasidone (20-120 mg/day) was well-tolerated with no new safety concerns and associated with continued improvement in depressive symptoms in this international sample of patients with bipolar depression. CLINICAL TRIAL REGISTRATION: JapicCTI-132319, clinicaltrials.gov - NCT01986114.

6.
Neuropsychiatr Dis Treat ; 16: 2943-2959, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33299316

RESUMO

Purpose: Consensus is lacking on the management of treatment-resistant depression (TRD), resulting in significant variations on how TRD patients are being managed in real-world practice. A survey explored how clinicians managed TRD across Asia, followed by an expert panel that interpreted the survey results and provided recommendations on how TRD could be managed in real-world clinical settings. Methods: Between March and July 2018, 246 clinicians from Hong Kong, Japan, Mainland China, South Korea, and Taiwan completed a survey related to their treatment approaches for TRD. Results: The survey showed physicians using more polytherapy (71%) compared to maintaining patients on monotherapy (29%). The most commonly (23%) administered polytherapy involved antidepressant augmentation with antipsychotics that 19% of physicians also indicated as their most important approach for managing TRD. The highest number of physicians (34%) ranked switching to another class of antidepressants as their most important approach, while 16% and 9% chose antidepressant combinations and electroconvulsive therapy (ECT), respectively. Conclusion: Taking into account the survey results, the expert panel made general recommendations on the management of TRD. TRD partial-responders to antidepressants should be considered for augmentation with second-generation antipsychotics. For non-responders, switching to another class of antidepressants ought to be considered. TRD patients achieving remission with acute treatment should consider continuing their antidepressants for at least another 6 months to prevent relapse. ECT is a treatment consideration for patients with severe depression or persistent symptoms despite multiple adequate trials of antidepressants. Physicians should also consider the response, tolerability and adherence to the current and previous antidepressants, the severity of symptoms, comorbidities, concomitant medications, preferences, and cost when choosing a TRD treatment approach for each individual patient.

7.
Front Genet ; 11: 519206, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33193604

RESUMO

The retrotransposon long interspersed nuclear element-1 (LINE-1) can autonomously increase its copy number within a host genome through the retrotransposition process. LINE-1 is active in the germline and in neural progenitor cells, and its somatic retrotransposition activity has a broad impact on neural development and susceptibility to neuropsychiatric disorders. The method to quantify the genomic copy number of LINE-1 would be important in unraveling the role of retrotransposition, especially in the brain. However, because of the species-specific evolution of LINE-1 sequences, methods for quantifying the copy number should be independently developed. Here, we developed a quantitative PCR (qPCR) assay to measure the copy number of active LINE-1 subfamilies in mice. Using the assay, we investigated aging-associated alterations of LINE-1 copy number in several brain regions in wild-type mice and Polg+/D257A mice as a model for accelerated aging. We found that aged Polg+/D257A mice showed higher levels of the type GfII LINE-1 in the basal ganglia than the wild-type mice did, highlighting the importance of assays that focus on an individual active LINE-1 subfamily.

8.
Transl Psychiatry ; 10(1): 407, 2020 Nov 24.
Artigo em Inglês | MEDLINE | ID: mdl-33235206

RESUMO

Previously, we reported a family in which bipolar disorder (BD) co-segregates with a Mendelian kidney disorder linked to 1q22. The causative renal gene was later identified as MUC1. Genome-wide linkage analysis of BD in the family yielded a peak at 1q22 that encompassed the NTRK1 and MUC1 genes. NTRK1 codes for TrkA (Tropomyosin-related kinase A) which is essential for development of the cholinergic nervous system. Whole genome sequencing of the proband identified a damaging missense mutation, E492K, in NTRK1. Induced pluripotent stem cells were generated from family members, and then differentiated to neural stem cells (NSCs). E492K NSCs had reduced neurite outgrowth. A conditional knock-in mouse line, harboring the point mutation in the brain, showed depression-like behavior in the tail suspension test following challenge by physostigmine, a cholinesterase inhibitor. These results are consistent with the cholinergic hypothesis of depression. They imply that the NTRK1 E492K mutation, impairs cholinergic neurotransmission, and may convey susceptibility to bipolar disorder.

9.
BMC Biol ; 18(1): 150, 2020 Oct 23.
Artigo em Inglês | MEDLINE | ID: mdl-33097039

RESUMO

BACKGROUND: The accumulation of mtDNA mutations in different tissues from various mouse models has been widely studied especially in the context of mtDNA mutation-driven ageing but has been confounded by the inherent limitations of the most widely used approaches. By implementing a method to sequence mtDNA without PCR amplification prior to library preparation, we map the full unbiased mtDNA mutation spectrum across six distinct brain regions from mice. RESULTS: We demonstrate that ageing-induced levels of mtDNA mutations (single nucleotide variants and deletions) reach stable levels at 50 weeks of age but can be further elevated specifically in the cortex, nucleus accumbens (NAc), and paraventricular thalamic nucleus (PVT) by expression of a proof-reading-deficient mitochondrial DNA polymerase, PolgD181A. The increase in single nucleotide variants increases the fraction of shared SNVs as well as their frequency, while characteristics of deletions remain largely unaffected. In addition, PolgD181A also induces an ageing-dependent accumulation of non-coding control-region multimers in NAc and PVT, a feature that appears almost non-existent in wild-type mice. CONCLUSIONS: Our data provide a novel view of the spatio-temporal accumulation of mtDNA mutations using very limited tissue input. The differential response of brain regions to a state of replication instability provides insight into a possible heterogenic mitochondrial landscape across the brain that may be involved in the ageing phenotype and mitochondria-associated disorders.

10.
Psychiatry Clin Neurosci ; 74(12): 635-644, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32827348

RESUMO

AIM: Previous studies conducted primarily in the USA and Europe have demonstrated the efficacy and safety of lurasidone 20-120 mg/day for the treatment of bipolar I depression. The aim of the current study was to evaluate the efficacy and safety of lurasidone monotherapy for the treatment of bipolar I depression among patients from diverse ethnic backgrounds, including those from Japan. METHODS: Patients were randomly assigned to double-blind treatment for 6 weeks with lurasidone, 20-60 mg/day (n = 184) or 80-120 mg/day (n = 169), or placebo (n = 172). The primary end-point was change from baseline to Week 6 on the Montgomery-Åsberg Depression Rating Scale (MADRS). RESULTS: Lurasidone treatment significantly reduced mean MADRS total scores from baseline to Week 6 for the 20-60-mg/day group (-13.6; adjusted P = 0.007; effect size = 0.33), but not for the 80-120-mg/day group (-12.6; adjusted P = 0.057; effect size = 0.22) compared with placebo (-10.6). Treatment with lurasidone 20-60 mg/day also improved MADRS response rates, functional impairment, and anxiety symptoms. The most common adverse events associated with lurasidone were akathisia and nausea. Lurasidone treatments were associated with minimal changes in weight, lipids, and measures of glycemic control. CONCLUSION: Monotherapy with once daily doses of lurasidone 20-60 mg, but not 80-120 mg, significantly reduced depressive symptoms and improved functioning in patients with bipolar I depression. Results overall were consistent with previous studies, suggesting that lurasidone 20-60 mg/day is effective and safe in diverse ethnic populations, including Japanese.

11.
Mol Psychiatry ; 25(11): 2695-2711, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32764691

RESUMO

Despite extensive genetic and neuroimaging studies, detailed cellular mechanisms underlying schizophrenia and bipolar disorder remain poorly understood. Recent progress in single-cell RNA sequencing (scRNA-seq) technologies enables identification of cell-type-specific pathophysiology. However, its application to psychiatric disorders is challenging because of methodological difficulties in analyzing human brains and the confounds due to a lifetime of illness. Brain organoids derived from induced pluripotent stem cells (iPSCs) of the patients are a powerful avenue to investigate the pathophysiological processes. Here, we generated iPSC-derived cerebral organoids from monozygotic twins discordant for psychosis. scRNA-seq analysis of the organoids revealed enhanced GABAergic specification and reduced cell proliferation following diminished Wnt signaling in the patient, which was confirmed in iPSC-derived forebrain neuronal cells. Two additional monozygotic twin pairs discordant for schizophrenia also confirmed the excess GABAergic specification of the patients' neural progenitor cells. With a well-controlled genetic background, our data suggest that unbalanced specification of excitatory and inhibitory neurons during cortical development underlies psychoses.

12.
Schizophr Bull ; 46(6): 1577-1586, 2020 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-32556264

RESUMO

Associations between altered DNA methylation of the serotonin transporter (5-HTT)-encoding gene SLC6A4 and early life adversity, mood and anxiety disorders, and amygdala reactivity have been reported. However, few studies have examined epigenetic alterations of SLC6A4 in schizophrenia (SZ). We examined CpG sites of SLC6A4, whose DNA methylation levels have been reported to be altered in bipolar disorder, using 3 independent cohorts of patients with SZ and age-matched controls. We found significant hypermethylation of a CpG site in SLC6A4 in male patients with SZ in all 3 cohorts. We showed that chronic administration of risperidone did not affect the DNA methylation status at this CpG site using common marmosets, and that in vitro DNA methylation at this CpG site diminished the promoter activity of SLC6A4. We then genotyped the 5-HTT-linked polymorphic region (5-HTTLPR) and investigated the relationship among 5-HTTLPR, DNA methylation, and amygdala volume using brain imaging data. We found that patients harboring low-activity 5-HTTLPR alleles showed hypermethylation and they showed a negative correlation between DNA methylation levels and left amygdala volumes. These results suggest that hypermethylation of the CpG site in SLC6A4 is involved in the pathophysiology of SZ, especially in male patients harboring low-activity 5-HTTLPR alleles.

13.
J Mol Endocrinol ; 64(3): 133-143, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31940281

RESUMO

Glucagon-like peptide-1 (GLP-1), secreted by gastrointestinal enteroendocrine L cells, induces insulin secretion and is important for glucose homeostasis. GLP-1 secretion is induced by various luminal nutrients, including amino acids. Intracellular Ca2+ and cAMP dynamics play an important role in GLP-1 secretion regulation; however, several aspects of the underlying mechanism of amino acid-induced GLP-1 secretion are not well characterized. We investigated the mechanisms underlying the L-glutamine-induced increase in Ca2+ and cAMP intracellular concentrations ([Ca2+]i and [cAMP]i, respectively) in murine enteroendocrine L cell line GLUTag cells. Application of L-glutamine to cells under low extracellular [Na+] conditions, which inhibited the function of the sodium-coupled L-glutamine transporter, did not induce an increase in [Ca2+]i. Application of G protein-coupled receptor family C group 6 member A and calcium-sensing receptor antagonist showed little effect on [Ca2+]i and [cAMP]i; however, taste receptor type 1 member 3 (TAS1R3) antagonist suppressed the increase in [cAMP]i. To elucidate the function of TAS1R3, which forms a heterodimeric umami receptor with taste receptor type 1 member 1 (TAS1R1), we generated TAS1R1 and TAS1R3 mutant GLUTag cells using the CRISPR/Cas9 system. TAS1R1 mutant GLUTag cells exhibited L-glutamine-induced increase in [cAMP]i, whereas some TAS1R3 mutant GLUTag cells did not exhibit L-glutamine-induced increase in [cAMP]i and GLP-1 secretion. These findings suggest that TAS1R3 is important for L-glutamine-induced increase in [cAMP]i and GLP-1 secretion. Thus, TAS1R3 may be coupled with Gs and related to cAMP regulation.

14.
FASEB J ; 34(1): 1465-1480, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31914590

RESUMO

Cardiolipin (CL) is a hallmark phospholipid of mitochondria and plays a significant role in maintaining the mitochondrial structure and functions. Despite the physiological importance of CL, mutant organisms, yeast, Arabidopsis, C elegans, and Drosophila, which lack CL synthase (Crls1) gene and consequently are deprived of CL, are viable. Here we report conditional Crls1-deficient mice using targeted insertion of loxP sequences flanking the functional domain of CRLS1 enzyme. Homozygous null mutant mice exhibited early embryonic lethality at the peri-implantation stage. We generated neuron-specific Crls1 knockout (cKO) mice by crossing with Camk2α-Cre mice. Neuronal loss and gliosis were gradually manifested in the forebrains, where CL levels were significantly decreased. In the surviving neurons, malformed mitochondria with bubble-like or onion-like inner membrane structures were observed. We showed decreased supercomplex assembly and reduced enzymatic activities of electron transport chain complexes in the forebrain of cKO mice, resulting in affected mitochondrial calcium dynamics, a slower rate of Ca2+ uptake and a smaller calcium retention capacity. These observations clearly demonstrate indispensable roles of CL as well as of Crls1 gene in mammals.


Assuntos
Sinalização do Cálcio , Cardiolipinas/metabolismo , Embrião de Mamíferos/metabolismo , Mitocôndrias/metabolismo , Neurônios/metabolismo , Prosencéfalo/embriologia , Animais , Cálcio/metabolismo , Cardiolipinas/genética , Embrião de Mamíferos/patologia , Camundongos , Camundongos Knockout , Mitocôndrias/genética , Mitocôndrias/patologia , Neurônios/patologia , Prosencéfalo/patologia , Transferases (Outros Grupos de Fosfato Substituídos)/deficiência , Transferases (Outros Grupos de Fosfato Substituídos)/metabolismo
16.
Sci Rep ; 9(1): 16506, 2019 11 11.
Artigo em Inglês | MEDLINE | ID: mdl-31712646

RESUMO

The paraventricular thalamic nucleus (PVT) is a part of epithalamus and sends outputs to emotion-related brain areas such as the medial prefrontal cortex, nucleus accumbens, and amygdala. Various functional roles of the PVT in emotion-related behaviors are drawing attention. Here, we investigated the effect of manipulation of PVT neurons on the firing patterns of medial prefrontal cortical (mPFC) neurons and depression-like behavior. Extracellular single-unit recordings revealed that acute activation of PVT neurons by hM3Dq, an activation type of designer receptors exclusively activated by designer drugs (DREADDs), and administration of clozapine N-oxide (CNO) caused firing rate changes in mPFC neurons. Moreover, chronic presynaptic inhibition in PVT neurons by tetanus toxin (TeTX) increased the proportion of interneurons among firing neurons in mPFC and shortened the immobility time in the forced swimming test, whereas long-term activation of PVT neurons by hM3Dq caused recurrent hypoactivity episodes. These findings suggest that PVT neurons regulate the excitation/inhibition balance in the mPFC and mood stability.


Assuntos
Depressão/etiologia , Depressão/psicologia , Transtorno Depressivo/etiologia , Transtorno Depressivo/psicologia , Núcleos da Linha Média do Tálamo/metabolismo , Núcleos da Linha Média do Tálamo/fisiopatologia , Terminações Pré-Sinápticas/metabolismo , Animais , Modelos Animais de Doenças , Fenômenos Eletrofisiológicos , Imuno-Histoquímica , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Ratos
17.
EMBO Mol Med ; 11(12): e10695, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31657521

RESUMO

Mice with the C3H background show greater behavioral propensity for schizophrenia, including lower prepulse inhibition (PPI), than C57BL/6 (B6) mice. To characterize as-yet-unknown pathophysiologies of schizophrenia, we undertook proteomics analysis of the brain in these strains, and detected elevated levels of Mpst, a hydrogen sulfide (H2 S)/polysulfide-producing enzyme, and greater sulfide deposition in C3H than B6 mice. Mpst-deficient mice exhibited improved PPI with reduced storage sulfide levels, while Mpst-transgenic (Tg) mice showed deteriorated PPI, suggesting that "sulfide stress" may be linked to PPI impairment. Analysis of human samples demonstrated that the H2 S/polysulfides production system is upregulated in schizophrenia. Mechanistically, the Mpst-Tg brain revealed dampened energy metabolism, while maternal immune activation model mice showed upregulation of genes for H2 S/polysulfides production along with typical antioxidative genes, partly via epigenetic modifications. These results suggest that inflammatory/oxidative insults in early brain development result in upregulated H2 S/polysulfides production as an antioxidative response, which in turn cause deficits in bioenergetic processes. Collectively, this study presents a novel aspect of the neurodevelopmental theory for schizophrenia, unraveling a role of excess H2 S/polysulfides production.


Assuntos
Sulfeto de Hidrogênio/metabolismo , Esquizofrenia/metabolismo , Esquizofrenia/fisiopatologia , Sulfetos/metabolismo , Animais , Eletroforese em Gel Bidimensional , Metabolismo Energético/genética , Metabolismo Energético/fisiologia , Epigenômica , Masculino , Camundongos , Proteômica , Esquizofrenia/genética , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz
18.
Psychiatry Clin Neurosci ; 73(9): 526-540, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31021488

RESUMO

Biological studies of bipolar disorder initially focused on the mechanism of action for antidepressants and antipsychotic drugs, and the roles of monoamines (e.g., serotonin, dopamine) have been extensively studied. Thereafter, based on the mechanism of action of lithium, intracellular signal transduction systems, including inositol metabolism and intracellular calcium signaling, have drawn attention. Involvement of intracellular calcium signaling has been supported by genetics and cellular studies. Elucidation of the neural circuits affected by calcium signaling abnormalities is critical, and our previous study suggested a role of the paraventricular thalamic nucleus. The genetic vulnerability of mitochondria causes calcium dysregulation and results in the hyperexcitability of serotonergic neurons, which are suggested to be susceptible to oxidative stress. Efficacy of anticonvulsants, animal studies of candidate genes, and studies using induced pluripotent stem cell-derived neurons have suggested a relation between bipolar disorder and the hyperexcitability of neurons. Recent genetic findings suggest the roles of polyunsaturated acids. At the systems level, social rhythm therapy targets circadian rhythm abnormalities, and cognitive behavioral therapy may target emotion/cognition (E/C) imbalance. In the future, pharmacological and psychosocial treatments may be combined and optimized based on the biological basis of each patient, which will realize individualized treatment.


Assuntos
Antidepressivos/uso terapêutico , Antimaníacos/uso terapêutico , Transtorno Bipolar/fisiopatologia , Transtorno Bipolar/terapia , Psicoterapia , Animais , Anticonvulsivantes/uso terapêutico , Antipsicóticos/uso terapêutico , Transtorno Bipolar/diagnóstico , Transtorno Bipolar/genética , Encéfalo/diagnóstico por imagem , Encéfalo/fisiopatologia , Sinalização do Cálcio , Terapia Cognitivo-Comportamental , Eletroconvulsoterapia , Eletroencefalografia , Neuroimagem Funcional , Humanos , Células-Tronco Pluripotentes Induzidas , Compostos de Lítio/uso terapêutico , Vias Neurais , Neurônios
20.
Antioxid Redox Signal ; 31(4): 275-317, 2019 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-30585734

RESUMO

Significance: Our current knowledge of the pathophysiology and molecular mechanisms causing psychiatric disorders is modest, but genetic susceptibility and environmental factors are central to the etiology of these conditions. Autism, schizophrenia, bipolar disorder and major depressive disorder show genetic gene risk overlap and share symptoms and metabolic comorbidities. The identification of such common features may provide insights into the development of these disorders. Recent Advances: Multiple pieces of evidence suggest that brain energy metabolism, mitochondrial functions and redox balance are impaired to various degrees in psychiatric disorders. Since mitochondrial metabolism and redox signaling can integrate genetic and environmental environmental factors affecting the brain, it is possible that they are implicated in the etiology and progression of psychiatric disorders. Critical Issue: Evidence for direct links between cellular mitochondrial dysfunction and disease features are missing. Future Directions: A better understanding of the mitochondrial biology and its intracellular connections to the nuclear genome, the endoplasmic reticulum and signaling pathways, as well as its role in intercellular communication in the organism, is still needed. This review focuses on the findings that implicate mitochondrial dysfunction, the resultant metabolic changes and oxidative stress as important etiological factors in the context of psychiatric disorders. We also propose a model where specific pathophysiologies of psychiatric disorders depend on circuit-specific impairments of mitochondrial dysfunction and redox signaling at specific developmental stages.


Assuntos
Transtornos Mentais/metabolismo , Mitocôndrias/metabolismo , Animais , Humanos , Oxirredução
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