Cognitive impairment in major depression and the mGlu2 receptor as a therapeutic target
Abstract
Cognitive impairment, in particular of attention and memory, is often reported by patients suffering from major depressive disorder (MDD) and deficits in attention are part of the current diagnostic criteria of MDD. Objectively measured cognitive deficits associated with MDD have been described in many studies. They have been conceptualized as an integral facet and epiphenomenon of MDD. However, evidence accumulated in recent years has challenged this notion and demonstrated that in a subset of patients the degree of cognitive deficits cannot be accounted for by the severity of depression. In addition, in some patients cognitive deficits persist despite resolution of depressive symptomatology. It is plausible to assume that cognitive deficits contribute to functional impairment even though supportive data for such a relationship are lacking. However, the exact association between cognitive deficits and major depression and the clinical and neurobiological characteristics of patients with MDD in whom cognitive deficits seem partially or fully independent of the clinical manifestation of depressive symptoms remain poorly understood. This review focuses on objective measures of non-emotional cognitive deficits in MDD and discusses the presence of a subgroup of patients in whom these symptoms can be defined independently and in dissociation from the rest of the depressive symptomatology. The current understanding of brain circuits and molecular events implicated in cognitive impairment in MDD are discussed with an emphasis on the missing elements that could further define the specificity of cognitive impairment in MDD and lead to new therapeutics. Furthermore, this article presents in detail observations made in behavioral studies in rodents with potential novel therapeutic agents, such as negative allosteric modulators at the metabotropic glutamate receptor type 2/3 (mGlu2/3 NAM) which exhibit both cognitive enhancing and antidepressant properties. Such a compound, RO4432717, was tested in tests of short term memory (delayed match to position), cognitive flexibility (Morris water maze, reversal protocol), impulsivity and compulsivity (5-choice serial reaction time) and spontaneous object recognition in rodents, providing first evidence of a profile potentially relevant to address cognitive impairment in MDD. This article is part of a Special Issue entitled 'Cognitive Enhancers'.
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The neurobiological underpinnings of cognitive functions share both overlapping and discrete features with those subserving mood regulation.
“Furthermore, in light of evidence suggesting that the neurobiological underpinnings of cognitive functions share both overlapping and discrete features with those subserving mood regulation, translational avenues of research are broadening the range of possible pharmacological novel targets relevant to cognitive dysfunction in MDD”
From Cognitive remission: a novel objective for the treatment of major depression? (2016) · cites this paper as [184]
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- Authors
- Goeldner, C., Ballard, T. M., Knoflach, F., Wichmann, J., Gatti, S., & Umbricht, D.
- Affiliations
- F. Hoffmann-La Roche AG (CH)
- Corresponding author
- Umbricht, Daniel
- Venue
- Neuropharmacology
- Publisher
- Elsevier BV
- Published
- 2013-01
- Volume
- 64
- Pages
- 337-346
- ISSN
- 0028-3908 (ISSN-L)
- OpenAlex
- W2049025142
- Cited by
- 96
- References
- 132
- Citations by year
- 2026: 1 · 2025: 4 · 2024: 6 · 2023: 3 · 2022: 8 · 2021: 5 · 2020: 4 · 2019: 6 · 2018: 10 · 2017: 11 · 2016: 9 · 2015: 14 · 2014: 7 · 2013: 8
- FWCI
- 1.06
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Neuropharmacology (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Keywords
- major depressive disorder, cognitive impairment, attention deficits, memory impairment, mGlu2/3 receptors, negative allosteric modulators, cognitive enhancement, antidepressant effects, cognitive flexibility, therapeutic target
- MeSH terms
- Animals, Antidepressive Agents, Cognition Disorders, Major Depressive Disorder, Hippocampus, Humans, Interneurons, Nerve Tissue Proteins, Receptors, Metabotropic Glutamate, Excitatory Amino Acid Agonists, Excitatory Amino Acid Antagonists, Nootropic Agents, Molecular Targeted Therapy, GABAergic Neurons
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