Cognitive remission: a novel objective for the treatment of major depression?

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Abstract

Background

Cognitive dysfunction in major depressive disorder (MDD) encompasses several domains, including but not limited to executive function, verbal memory, and attention. Furthermore, cognitive dysfunction is a frequent residual manifestation in depression and may persist during the remitted phase. Cognitive deficits may also impede functional recovery, including workforce performance, in patients with MDD. The overarching aims of this opinion article are to critically evaluate the effects of available antidepressants as well as novel therapeutic targets on neurocognitive dysfunction in MDD.

Discussion

Conventional antidepressant drugs mitigate cognitive dysfunction in some people with MDD. However, a significant proportion of MDD patients continue to experience significant cognitive impairment. Two multicenter randomized controlled trials (RCTs) reported that vortioxetine, a multimodal antidepressant, has significant precognitive effects in MDD unrelated to mood improvement. Lisdexamfetamine dimesylate was shown to alleviate executive dysfunction in an RCT of adults after full or partial remission of MDD. Preliminary evidence also indicates that erythropoietin may alleviate cognitive dysfunction in MDD. Several other novel agents may be repurposed as cognitive enhancers for MDD treatment, including minocycline, insulin, antidiabetic agents, angiotensin-converting enzyme inhibitors, S-adenosyl methionine, acetyl-L-carnitine, alpha lipoic acid, omega-3 fatty acids, melatonin, modafinil, galantamine, scopolamine, N-acetylcysteine, curcumin, statins, and coenzyme Q10.

Summary

The management of cognitive dysfunction remains an unmet need in the treatment of MDD. However, it is hoped that the development of novel therapeutic targets will contribute to ‘cognitive remission’, which may aid functional recovery in MDD.

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Most cited references 163

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A meta-analysis of cognitive deficits in first-episode Major Depressive Disorder.

Rico Lee, Daniel F. Hermens, Melanie A Porter … (2012)

Recurrent-episode Major Depressive Disorder (MDD) is associated with a number of neuropsychological deficits. To date, less is known about whether these are present in the first-episode. The current aim was to systematically evaluate the literature on first-episode MDD to determine whether cognition may be a feasible target for early identification and intervention. Electronic database searches were conducted to examine neuropsychological studies in adults (mean age greater than 18 years old) with a first-episode of MDD. Effect sizes were pooled by cognitive domain. Using meta-regression techniques, demographic and clinical factors potentially influencing heterogeneity of neuropsychological outcome were also investigated. The 15 independent samples reviewed yielded data for 644 patients with a mean age of 39.36 years (SD=10.21). Significant cognitive deficits were identified (small to medium effect sizes) for psychomotor speed, attention, visual learning and memory, and all aspects of executive functioning. Symptom remission, inpatient status, antidepressant use, age and educational attainment, each significantly contributed to heterogeneity in effect sizes in at least one cognitive domain. Reviewed studies were limited by small sample sizes and often did not report important demographic and clinical characteristics of patients. The current meta-analysis was the first to systematically demonstrate reduced neuropsychological functioning in first-episode MDD. Psychomotor speed and memory functioning were associated with clinical state, whereas attention and executive functioning were more likely trait-markers. Demographic factors were also associated with heterogeneity across studies. Overall, cognitive deficits appear to be feasible early markers and targets for early intervention in MDD. Copyright © 2011 Elsevier B.V. All rights reserved.

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The chemistry and biological activities of N-acetylcysteine.

Yuval Samuni, Sara Goldstein, Olivia Dean … (2013)

N-acetylcysteine (NAC) has been in clinical practice for several decades. It has been used as a mucolytic agent and for the treatment of numerous disorders including paracetamol intoxication, doxorubicin cardiotoxicity, ischemia-reperfusion cardiac injury, acute respiratory distress syndrome, bronchitis, chemotherapy-induced toxicity, HIV/AIDS, heavy metal toxicity and psychiatric disorders. The mechanisms underlying the therapeutic and clinical applications of NAC are complex and still unclear. The present review is focused on the chemistry of NAC and its interactions and functions at the organ, tissue and cellular levels in an attempt to bridge the gap between its recognized biological activities and chemistry. The antioxidative activity of NAC as of other thiols can be attributed to its fast reactions with OH, NO2, CO3(-) and thiyl radicals as well as to restitution of impaired targets in vital cellular components. NAC reacts relatively slowly with superoxide, hydrogen-peroxide and peroxynitrite, which cast some doubt on the importance of these reactions under physiological conditions. The uniqueness of NAC is most probably due to efficient reduction of disulfide bonds in proteins thus altering their structures and disrupting their ligand bonding, competition with larger reducing molecules in sterically less accessible spaces, and serving as a precursor of cysteine for GSH synthesis. The outlined reactions only partially explain the diverse biological effects of NAC, and further studies are required for determining its ability to cross the cell membrane and the blood-brain barrier as well as elucidating its reactions with components of cell signaling pathways. Copyright © 2013 Elsevier B.V. All rights reserved.

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Evidence for a cytokine model of cognitive function.

J McAfoose, B.T. Baune (2009)

Aiming at a formulation of a cytokine model of cognitive function under immunologically unchallenged physiological conditions, this article reviews the cytokine biology in the central nervous system (CNS) and recent developments in normal cytokine functions within the CNS that subserve cognitive processes. Currently available evidence shows that the cytokines IL-1beta, IL-6 and TNF-alpha play a role in complex cognitive processes at the molecular level, such as synaptic plasticity, neurogenesis, as well as neuromodulation. Such findings provide evidence for a cytokine model of cognitive function, which shows that cytokines play an intimate role in the molecular and cellular mechanisms subserving learning, memory and cognition under physiological conditions. These cytokine-mediated cognitive processes have implications in the long-term development and pathogenesis of specific neuropsychiatric disorders such as major depression and dementia. The identification of this central role of cytokines in various brain activities during health provides greater insight into normal brain functions, especially synaptic plasticity, memory and cognition, and facilitates the understanding of specific biological mechanisms involved in neuropsychiatric diseases, such as dementia and depression. In order to extend the suggested cytokine model of cognitive function onto other members of the cytokine family, future research is required to investigate the physiological effects of other cytokines such as interferon-gamma (IFNgamma), alpha(1)-antichymotrypsin and IL-2 on cognitive function at the molecular level under immunologically unchallenged conditions.

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Author and article information

Contributors

André F. Carvalho: +55 85 3261 7227 , andrefc7@terra.com.br

Journal

Journal ID (nlm-ta): BMC Med

Journal ID (iso-abbrev): BMC Med

Title: BMC Medicine

Publisher: BioMed Central (London )

ISSN (Electronic): 1741-7015

Publication date (Electronic): 22 January 2016

Publication date PMC-release: 22 January 2016

Publication date Collection: 2016

Volume: 14

Electronic Location Identifier: 9

Affiliations

[ ]Department of Neurosciences, University of Padova, Padova, Italy

[ ]Psychiatric Centre Copenhagen, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark

[ ]Translational Psychiatry Research Group and Department of Clinical Medicine, Faculty Medicine, Federal University of Ceará, Rua Prof. Costa Mendes 1608, 4° andar, Fortaleza, CE 60430-040 Brazil

[ ]Deakin University, School of Medicine, IMPACT Strategic Research Centre, Geelong, Australia

[ ]Department of Psychiatry, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand

[ ]Laboratory of Calcium Binding Proteins in the Central Nervous System, Department of Biochemistry, Federal University of Rio Grande do Sul, UFRGS, Porto Alegre, Brazil

[ ]Orygen, The National Centre of Excellence in Youth Mental Health, Department of Psychiatry and The Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, Australia

Article

Publisher ID: 560

DOI: 10.1186/s12916-016-0560-3

PMC ID: 4724131

PubMed ID: 26801406

SO-VID: cffdf025-2d3a-4790-a8ff-4d363db4913f

License:

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 9 November 2015

Date accepted : 7 January 2016

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ScienceOpen disciplines: Medicine

Keywords: antidepressants,cognition,cognitive enhancers,erythropoietin,lisdexamfetamine dimesylate,major depression,novel targets,vortioxetine,psychiatry

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ScienceOpen disciplines: Medicine

Keywords: antidepressants, cognition, cognitive enhancers, erythropoietin, lisdexamfetamine dimesylate, major depression, novel targets, vortioxetine, psychiatry

Cognitive remission: a novel objective for the treatment of major depression?

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Abstract

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Measurement of Glucocorticoid Receptor Signaling in Major Depression

Most cited references 163

A meta-analysis of cognitive deficits in first-episode Major Depressive Disorder.

The chemistry and biological activities of N-acetylcysteine.

Evidence for a cytokine model of cognitive function.

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