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Cognitive Dysfunction in Depression – Pathophysiology and Novel Targets
Open accessAbstract
Major depressive disorder (MDD) is associated with cognitive dysfunction encompassing several domains, including memory, executive function, processing speed and attention. Cognitive deficits persist in a significant proportion of patients even in remission, compromising psychosocial functioning and workforce performance. While monoaminergic antidepressants may improve cognitive performance in MDD, most antidepressants have limited clinical efficacy. The overarching aims of this review were: (1) to synthesize extant literature on putative biological pathways related to cognitive dysfunction in MDD and (2) to review novel neurotherapeutic targets for cognitive enhancement in MDD. We found that reciprocal and overlapping biological pathways may contribute to cognitive dysfunction in MDD, including an hyperactive hypothalamic-pituitary-adrenal axis, an increase in oxidative and nitrosative stress, inflammation (e.g., enhanced production of pro-inflammatory cytokines), mitochondrial dysfunction, increased apoptosis as well as a diminished neurotrophic support. Several promising neurotherapeutic targets were identified such as minocycline, statins, anti-inflammatory compounds, N-acetylcysteine, omega-3 poliunsaturated fatty acids, erythropoietin, thiazolidinediones, glucagon-like peptide-1 analogues, S-adenosyl-l-methionine (SAMe), cocoa flavonols, creatine monohydrate and lithium. Erythropoietin and SAMe had pro-cognitive effects in randomized controlled trials (RCT) involving MDD patients. Despite having preclinical and/or preliminary evidences from trials suggesting possible efficacy as novel cognitive enhancing agents for MDD, no RCT to date was performed for most of the other therapeutic targets reviewed herein. In conclusion, multiple biological pathways are involved in cognitive dysfunction in MDD. RCTs testing genuinely novel pro-cognitive compounds for MDD are warranted.
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“In addition, a significant proportion of patients with MDD do not recover baseline levels of psychosocial functioning even when they meet the conventional definition of remission (e.g. a score ≤7 on the Hamilton Depression Rating Scale (HDRS)) [2, 11, 12], suggesting that non-affective dimensions and domains are critical determinants of functional outcome.”
From Cognitive remission: a novel objective for the treatment of major depression? (2016) · cites this paper as [11]
In the citing paper
“Only a subset of individuals with MDD (30–40 %) reach symptomatic remission after adequate treatment with a first-line antidepressant, and many patients do not reach premorbid levels of psychosocial functioning, such that a significant proportion of patients present residual symptoms.”
From Cognitive remission: a novel objective for the treatment of major depression? (2016) · cites this paper as [11]
In the citing paper
“Several mechanisms may contribute to cognitive dysfunction in MDD, including but not limited to an over-activation of the hypothalamic–pituitary–adrenal axis, oxidative and nitrosative stress, imbalances in pathways involved in cell survival and death, and immune activation [11].”
From Cognitive remission: a novel objective for the treatment of major depression? (2016) · cites this paper as [11]
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BackgroundCognitive remission: a novel objective for the treatment of major depression?
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Self-citation
Metadata
- Authors
- Carvalho, A., Miskowiak, K., Hyphantis, T., Kohler, C., Alves, G., Bortolato, B., G. Sales, P., Machado-Vieira, R., Berk, M., & McIntyre, R.
- Affiliations
- Universidade Federal do Ceará (BR)
- Corresponding author
- McIntyre, Roger
- Venue
- CNS & Neurological Disorders - Drug Targets
- Publisher
- Bentham Science Publishers Ltd.
- Published
- 2015-01-22
- Volume
- 13
- Issue
- 10
- Pages
- 1819-1835
- ISSN
- 1568-007X (ISSN-L)
- 1871-5273
- OpenAlex
- W2150071717
- Cited by
- 107
- References
- 252
- Citations by year
- 2026: 3 · 2025: 5 · 2024: 10 · 2023: 7 · 2022: 12 · 2021: 13 · 2020: 4 · 2019: 9 · 2018: 12 · 2017: 9 · 2016: 17 · 2015: 6
- FWCI
- 10.62
- Type
- journal article
- Language
- en
- Open access
- green
- figshare.com
- Licence
- cc-by
- Locations
- CNS & Neurological Disorders - Drug Targets (publishedVersion)
- PubMed (publishedVersion)
- Deakin Research Online (Deakin University) (submittedVersion)
- Figshare (submittedVersion, cc-by)
- Topics
- Health Sciences › Medicine › Pharmacology (medical) › Treatment of Major Depression
- Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
- Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
- Keywords
- major depressive disorder, cognitive impairment, cognitive enhancement, hypothalamic-pituitary-adrenal axis, oxidative stress, nitrosative stress, neuroinflammation, inflammatory cytokines, mitochondrial dysfunction, apoptosis, neurotrophic support, minocycline, statins, N-acetylcysteine, omega-3 polyunsaturated fatty acids, erythropoietin, S-adenosylmethionine, creatine monohydrate, lithium, thiazolidinediones, glucagon-like peptide-1 analogues
- MeSH terms
- Cognition Disorders, Depression, Humans, Nootropic Agents
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