The molecular pathophysiology of depression and the new therapeutics

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Abstract

Major depressive disorder (MDD) is a highly prevalent and disabling disorder. Despite the many hypotheses proposed to understand the molecular pathophysiology of depression, it is still unclear. Current treatments for depression are inadequate for many individuals, because of limited effectiveness, delayed efficacy (usually two weeks), and side effects. Consequently, novel drugs with increased speed of action and effectiveness are required. Ketamine has shown to have rapid, reliable, and long‐lasting antidepressant effects in treatment‐resistant MDD patients and represent a breakthrough therapy for patients with MDD; however, concerns regarding its efficacy, potential misuse, and side effects remain. In this review, we aimed to summarize molecular mechanisms and pharmacological treatments for depression. We focused on the fast antidepressant treatment and clarified the safety, tolerability, and efficacy of ketamine and its metabolites for the MDD treatment, along with a review of the potential pharmacological mechanisms, research challenges, and future clinical prospects.

Abstract

This review aimed to clarify the safety, tolerability, and efficacy of ketamine and its metabolites for the treatment of major depressive disorder (MDD), along with a review of potential pharmacological mechanisms, research challenges, and future clinical prospects. Many novel hubba proteins and MDD‐risk proteins were found, indicating that the current pharmacological mechanisms were just the tip of the iceberg.

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The role of inflammation in depression: from evolutionary imperative to modern treatment target.

Andrew Miller, Charles L. Raison (2016)

Crosstalk between inflammatory pathways and neurocircuits in the brain can lead to behavioural responses, such as avoidance and alarm, that are likely to have provided early humans with an evolutionary advantage in their interactions with pathogens and predators. However, in modern times, such interactions between inflammation and the brain appear to drive the development of depression and may contribute to non-responsiveness to current antidepressant therapies. Recent data have elucidated the mechanisms by which the innate and adaptive immune systems interact with neurotransmitters and neurocircuits to influence the risk for depression. Here, we detail our current understanding of these pathways and discuss the therapeutic potential of targeting the immune system to treat depression.

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Genome-wide association analyses identify 44 risk variants and refine the genetic architecture of major depression

Naomi R. Wray, Stephan Ripke, Manuel Mattheisen … (2018)

Major depressive disorder (MDD) is a common illness accompanied by considerable morbidity, mortality, costs, and heightened risk of suicide. We conducted a genome-wide association (GWA) meta-analysis based in 135,458 cases and 344,901 control, We identified 44 independent and significant loci. The genetic findings were associated with clinical features of major depression, and implicated brain regions exhibiting anatomical differences in cases. Targets of antidepressant medications and genes involved in gene splicing were enriched for smaller association signal. We found important relations of genetic risk for major depression with educational attainment, body mass, and schizophrenia: lower educational attainment and higher body mass were putatively causal whereas major depression and schizophrenia reflected a partly shared biological etiology. All humans carry lesser or greater numbers of genetic risk factors for major depression. These findings help refine and define the basis of major depression and imply a continuous measure of risk underlies the clinical phenotype.

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Genome-wide meta-analysis of depression identifies 102 independent variants and highlights the importance of the prefrontal brain regions

David M. Howard, Mark J. Adams, Toni‐Kim Clarke … (2019)

Major depression is a debilitating psychiatric illness that is typically associated with low mood and anhedonia. Depression has a heritable component that has remained difficult to elucidate with current sample sizes due to the polygenic nature of the disorder. To maximize sample size, we meta-analyzed data on 807,553 individuals (246,363 cases and 561,190 controls) from the three largest genome-wide association studies of depression. We identified 102 independent variants, 269 genes, and 15 genesets associated with depression, including both genes and gene pathways associated with synaptic structure and neurotransmission. An enrichment analysis provided further evidence of the importance of prefrontal brain regions. In an independent replication sample of 1,306,354 individuals (414,055 cases and 892,299 controls), 87 of the 102 associated variants were significant after multiple testing correction. These findings advance our understanding of the complex genetic architecture of depression and provide several future avenues for understanding etiology and developing new treatment approaches.

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Author and article information

Contributors

Jia Xu: xujia@nbu.edu.cn

Chuang Wang: wangchuang@nbu.edu.cn

Journal

Journal ID (nlm-ta): MedComm (2020)

Journal ID (iso-abbrev): MedComm (2020)

Journal ID (doi): 10.1002/(ISSN)2688-2663

Journal ID (publisher-id): MCO2

Title: MedComm

Publisher: John Wiley and Sons Inc. (Hoboken )

ISSN (Electronic): 2688-2663

Publication date (Electronic): 21 July 2022

Publication date Collection: September 2022

Volume: 3

Issue: 3 ( doiID: 10.1002/mco2.v3.3 )

Electronic Location Identifier: e156

Affiliations

[ ¹ ] Ningbo Key Laboratory of Behavioral Neuroscience Ningbo University School of Medicine Ningbo Zhejiang China

[ ² ] Zhejiang Provincial Key Laboratory of Pathophysiology School of Medicine Ningbo University Ningbo Zhejiang China

[ ³ ] Department of Physiology and Pharmacology Ningbo University School of Medicine Ningbo Zhejiang China

[ ⁴ ] Department of Laboratory Medicine Ningbo Kangning Hospital Ningbo Zhejiang China

[ ⁵ ] Department of Child Psychiatry Ningbo Kanning Hospital Ningbo Zhejiang China

Author notes

[*] [* ] Correspondence

Chuang Wang and Jia Xu, Ningbo Key Laboratory of Behavioral Neuroscience, Ningbo University School of Medicine, 818 Fenghua Road, Ningbo, Zhejiang 315211, China.

Email: wangchuang@ 123456nbu.edu.cn and xujia@ 123456nbu.edu.cn

[#]

Haihua Tian and Zhenyu Hu contributed equally to this work.

Article

Publisher ID: MCO2156

DOI: 10.1002/mco2.156

PMC ID: 9301929

PubMed ID: 35875370

SO-VID: 1821f6fe-344d-458e-a3f8-d6a571984991

License:

This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

History

Date revision received : 06 June 2022

Date received : 18 February 2022

Date accepted : 06 June 2022

Page count

Figures: 6, Tables: 3, Pages: 36, Words: 20826

Funding

Funded by: Natural Science Funds for Distinguished Young Scholar of Zhejiang

Award ID: LR20H090001

Funded by: National Natural Science Foundation of China , doi 10.13039/501100001809;

Award ID: 82171527

Funded by: Ningbo Health Branding Subject Fund

Award ID: PPXK2018‐08

Funded by: Medical Science and Technology Project of Zhejiang Province , doi 10.13039/501100017594;

Award ID: 2019KY628

Funded by: Natural Science Foundation of Zhejiang Province , doi 10.13039/501100004731;

Award ID: LY21H090003

Funded by: Natural Science Foundation of Ningbo , doi 10.13039/100007834;

Award ID: 2019A61029

Funded by: Medical Science and Technology Project in Ningbo

Award ID: 2020Y20

Funded by: This project is also sponsored by KC Magna funded in Ningbo University

Custom metadata

source-schema-version-number 2.0

cover-date September 2022

details-of-publishers-convertor Converter:WILEY_ML3GV2_TO_JATSPMC version:6.1.7 mode:remove_FC converted:21.07.2022

Keywords: (r)‐ketamine,(s)‐ketamine,ketamine,major depressive disorder (mdd)

Data availability:

Keywords: (r)‐ketamine, (s)‐ketamine, ketamine, major depressive disorder (mdd)

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The molecular pathophysiology of depression and the new therapeutics

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Most cited references 387

The role of inflammation in depression: from evolutionary imperative to modern treatment target.

Genome-wide association analyses identify 44 risk variants and refine the genetic architecture of major depression

Genome-wide meta-analysis of depression identifies 102 independent variants and highlights the importance of the prefrontal brain regions

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