Complex psychiatry最新文献

Major depressive disorder (MDD) is a complex and multifactorial psychiatric disorder that causes serious health, social, and economic concerns worldwide. The main treatment of the symptoms is through antidepressant (AD) drugs. However, not all patients respond properly to these drugs. Omic sciences are widely used to analyze not only biomarkers for the AD response but also their molecular mechanism. In this review, we aimed to focus on omics data to better understand the molecular mechanisms involving AD effects on MDD. We consistently found, from preclinical to clinical data, that glutamatergic transmission, immune/inflammatory processes, energy metabolism, oxidative stress, and lipid metabolism were associated with traditional and potential new ADs. Despite efforts of studies investigating biomarkers of response to ADs, which could contribute to personalized treatment, there is no biomarker panel available for clinical application. From clinical genomic studies, we found that the main findings contribute to the development of pharmacogenomic tests for AD efficacy for each patient. Several studies pointed at DRD2, PXDNL, CACNA1E, and CACNA2D1 genes as potential targets for MDD treatment and the efficacy and rapid-antidepressant effect of ketamine. Finally, more in-depth studies of the molecular targets pointed here are needed to determine the clinical relevance and provide further evidence for precision MDD treatment.

No large-scale genome-wide association studies (GWASs) of psychosis have been conducted in Mexico or Latin America to date. Schizophrenia and bipolar disorder in particular have been found to be highly heritable and genetically influenced. However, understanding of the biological basis of psychosis in Latin American populations is limited as previous genomic studies have almost exclusively relied on participants of Northern European ancestry. With the goal of expanding knowledge on the genomic basis of psychotic disorders within the Mexican population, the National Institute of Psychiatry Ramón de la Fuente Muñiz (INPRFM), the Harvard T.H. Chan School of Public Health, and the Broad Institute's Stanley Center for Psychiatric Research launched the Neuropsychiatric Genetics Research of Psychosis in Mexican Populations (NeuroMex) project to collect and analyze case-control psychosis samples from 5 states across Mexico. This article describes the planned sample collection and GWAS protocol for the NeuroMex study. The 4-year study will span from April 2018 to 2022 and aims to recruit 9,208 participants: 4,604 cases and 4,604 controls. Study sites across Mexico were selected to ensure collected samples capture the genomic diversity within the Mexican population. Blood samples and phenotypic data will be collected during the participant interview process and will contribute to the development of a local biobank in Mexico. DNA extraction will be done locally and genetic analysis will take place at the Broad Institute in Cambridge, MA. We will collect extensive phenotypic information using several clinical scales. All study materials including phenotypic instruments utilized are openly available in Spanish and English. The described study represents a long-term collaboration of a number of institutions from across Mexico and the Boston area, including clinical psychiatrists, clinical researchers, computational biologists, and managers at the 3 collaborating institutions. The development of relevant data management, quality assurance, and analysis plans are the primary considerations in this protocol article. Extensive management and analysis processes were developed for both the phenotypic and genetic data collected. Capacity building, partnerships, and training between and among the collaborating institutions are intrinsic components to this study and its long-term success.

Response to lithium varies widely between individuals with bipolar disorder (BD). Polygenic risk scores (PRSs) can uncover pharmacogenomics effects and may help predict drug response. Patients (N = 2,510) with BD were assessed for long-term lithium response in the Consortium on Lithium Genetics using the Retrospective Criteria of Long-Term Treatment Response in Research Subjects with Bipolar Disorder score. PRSs for attention-deficit/hyperactivity disorder (ADHD), major depressive disorder (MDD), and schizophrenia (SCZ) were computed using lassosum and in a model including all three PRSs and other covariates, and the PRS of ADHD (β = -0.14; 95% confidence interval [CI]: -0.24 to -0.03; p value = 0.010) and MDD (β = -0.16; 95% CI: -0.27 to -0.04; p value = 0.005) predicted worse quantitative lithium response. A higher SCZ PRS was associated with higher rates of medication nonadherence (OR = 1.61; 95% CI: 1.34-1.93; p value = 2e-7). This study indicates that genetic risk for ADHD and depression may influence lithium treatment response. Interestingly, a higher SCZ PRS was associated with poor adherence, which can negatively impact treatment response. Incorporating genetic risk of ADHD, depression, and SCZ in combination with clinical risk may lead to better clinical care for patients with BD.

The ANK3 locus has been repeatedly found to confer an increased risk for bipolar disorder. ANK3 codes for Ankyrin-G (Ank-G), a scaffold protein concentrated at axon initial segments, nodes of Ranvier, and dendritic spines, where it organizes voltage-gated sodium and potassium channels and cytoskeletal proteins. Mice with homozygous conditional knockout of Ank-G in the adult forebrain display hyperactivity and reduced anxiety-like behaviors, responsive to mood stabilizers. Their behavior switches to a depression-like phenotype when exposed to chronic social defeat stress (SDS), and then spontaneously reverts to baseline hyperactivity. Ank-G heterozygous conditional knockouts (Ank-G Het cKO) have not previously been characterized. Here, we describe the behavior of Ank-G Het cKO mice compared to littermate controls in the open field, elevated plus maze, and forced swim test, under both unstressed and stressed conditions. We found that Ank-G Het cKO is not significantly different from controls at baseline or after chronic SDS. The chronic stress-induced "depression-like" behavioral phenotype is persistent for at least 28 days and is responsive to fluoxetine. Strikingly, Ank-G Het cKO mice display increased sensitivity to a short duration SDS, which does not affect controls. The heterozygous Ank-G genetic model may provide novel insights into the role of Ank-G in the pathophysiology of stress sensitivity and "depression-like" phenotypes and could be useful for studying Ank-G-related gene-environment interactions.

The kynurenine pathway (KP) is a major route for L-tryptophan (L-TRP) metabolism, yielding a variety of bioactive compounds including kynurenic acid (KYNA), 3-hydroxykynurenine (3-HK), quinolinic acid (QUIN), and picolinic acid (PIC). These tryptophan catabolites are involved in the pathogenesis of many neuropsychiatric disorders, particularly when the KP becomes dysregulated. Accordingly, the enzymes that regulate the KP such as indoleamine 2,3-dioxygenase (IDO)/tryptophan 2,3-dioxygenase, kynurenine aminotransferases (KATs), and kynurenine 3-monooxygenase (KMO) represent potential drug targets as enzymatic inhibition can favorably rebalance KP metabolite concentrations. In addition, the galantamine-memantine combination, through its modulatory effects at the alpha7 nicotinic acetylcholine receptors and N-methyl-D-aspartate receptors, may counteract the effects of KYNA. The aim of this review is to highlight the effectiveness of IDO-1, KAT II, and KMO inhibitors, as well as the galantamine-memantine combination in the modulation of different KP metabolites. KAT II inhibitors are capable of decreasing the KYNA levels in the rat brain by a maximum of 80%. KMO inhibitors effectively reduce the central nervous system (CNS) levels of 3-HK, while markedly boosting the brain concentration of KYNA. Emerging data suggest that the galantamine-memantine combination also lowers L-TRP, kynurenine, KYNA, and PIC levels in humans. Presently, there are only 2 pathophysiological mechanisms (cholinergic and glutamatergic) that are FDA approved for the treatment of cognitive dysfunction for which purpose the galantamine-memantine combination has been designed for clinical use against Alzheimer's disease. The alpha7 nicotinic-NMDA hypothesis targeted by the galantamine-memantine combination has been implicated in the pathophysiology of various CNS diseases. Similarly, KYNA is well capable of modulating the neuropathophysiology of these disorders. This is known as the KYNA-centric hypothesis, which may be implicated in the management of certain neuropsychiatric conditions. In line with this hypothesis, KYNA may be considered as the "conductor of the orchestra" for the major pathophysiological mechanisms underlying CNS disorders. Therefore, there is great opportunity to further explore and compare the biological effects of these therapeutic modalities in animal models with a special focus on their effects on KP metabolites in the CNS and with the ultimate goal of progressing to clinical trials for many neuropsychiatric diseases.