The DOI matches its Crossref record; 75 of the 79 references it cites were found in a registry or an index; none of the 87 sources its claims cite is checked for support yet.
Cognitive impairment in major depressive disorder
Open accessAbstract
Cognitive dysfunction is a symptomatic domain identified across many mental disorders. Cognitive deficits in individuals with major depressive disorder (MDD) contribute significantly to occupational and functional disability. Notably, cognitive subdomains such as learning and memory, executive functioning, processing speed, and attention and concentration are significantly impaired during, and between, episodes in individuals with MDD. Most antidepressants have not been developed and/or evaluated for their ability to directly and independently ameliorate cognitive deficits. Multiple interacting neurobiological mechanisms (eg, neuroinflammation) are implicated as subserving cognitive deficits in MDD. A testable hypothesis, with preliminary support, posits that improving performance across cognitive domains in individuals with MDD may improve psychosocial function, workplace function, quality of life, and other patient-reported outcomes, independent of effects on core mood symptoms. Herein we aim to (1) provide a rationale for prioritizing cognitive deficits as a therapeutic target, (2) briefly discuss the neurobiological substrates subserving cognitive dysfunction, and (3) provide an update on current and future treatment avenues.
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72 Not checked yet · 8 Own interpretation · 1 No basis given
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In the paper
“Results from the International Mood Disorders Collaborative Project (IMDCP), a collaborative effort between the University of Toronto and Cleveland Clinic, indicated that cognitive function is a greater determinant of overall workplace function than measures of depression severity among working adults with MDD.”
§ Cognitive impairment in major depressive disorder > Cognition: Implications of Function
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
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In the paper
“Vice versa, functional impairments can also contribute to the persistence of cognitive symptoms in MDD. 9”
§ Cognitive impairment in major depressive disorder > Introduction
What the sources say
- Not checked yetcites [9] source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Hitherto, only 2 antidepressants (ie, duloxetine and vortioxetine) have demonstrated direct, independent, and clinically relevant effects on cognitive dysfunction in MDD. 8”
§ Cognitive impairment in major depressive disorder > Introduction
What the sources say
- Not checked yetcites [8] source
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“Cognitive deficits in individuals with major depressive disorder (MDD) contribute significantly to occupational and functional disability.”
- Also stated in: § Introduction · boosted
“Many studies have shown that cognitive dysfunction, in particular, is a powerful predictor of occupational and social functional impairment in adults with MDD.[5][6][7]”
§ Cognitive impairment in major depressive disorder > Abstract
What the sources say
- Not checked yetcites [5][6][7]
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Also stated in: § Introduction · boosted
None of the sources cited for this claim have been checked yet.
In the paper
“The trifecta of cognitive dysfunction, anhedonia, and depressed mood is thought to be a critical mediator of MDD-related functional disability.6,11”
§ Cognitive impairment in major depressive disorder > Introduction
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
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None of the sources cited for this claim have been checked yet.
In the paper
“Indeed, individuals with inflammatory and metabolic comorbidities are at greater risks of mood disorders and cognitive dysfunction.13,14”
§ Cognitive impairment in major depressive disorder > Introduction
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
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In the paper
“The persistence of cognitive deficits after remission of depressive symptoms has been shown to contribute to the failure in achieving full functional recovery in MDD. 5”
§ Cognitive impairment in major depressive disorder > Introduction
What the sources say
- Not checked yetcites [5] source
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
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None of the sources cited for this claim have been checked yet.
In the paper
“Disparate neurobiological systems, including, but not limited to, arousal, mood, impulsivity, reward, anhedonia, energy, fatigue, and suicidality, all contribute to cognitive changes in MDD.16,17”
§ Cognitive impairment in major depressive disorder > Cognition: Glossary
What the sources say
- Not checked yetcites [16] source
- Not checked yetcites [17]
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“Neurochemical changes (eg, catecholaminergic disturbances) have also been implicated as a mediator of cognitive dysfunction in MDD. 26”
§ Cognitive impairment in major depressive disorder > Cognition: Neurobiology
What the sources say
- Not checked yetcites [26] source
hedgedconditional- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“There is wide recognition of reciprocal relationships between mood, cognition, and metabolic disorders.38”
§ Cognitive impairment in major depressive disorder > Cognition: Neurobiology
What the sources say
- Not checked yetcites [38] source
boostedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- It may state two separate claims as one. 11
- Probably not a substantial claim. 6
- The quote only partly states this claim. 1
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Notably, cognitive subdomains such as learning and memory, executive functioning, processing speed, and attention and concentration are significantly impaired during, and between, episodes in individuals with MDD.”
§ Cognitive impairment in major depressive disorder > Abstract
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: unclear — It is unclear why the paper says it holds.
It may state two separate claims as one.
In the paper
“Disturbances in concentration, executive function, decision-making, and learning and memory are part of the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5) items that determine whether an individual meets criteria for cognitive dysfunction in MDD.6”
§ Cognitive impairment in major depressive disorder > Cognition: Glossary
What the sources say
- Not checked yetcites [6] source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“Moreover, cognitive dysfunction in MDD has been proposed to be an endophenotype that worsens as a function of episode frequency.9,10”
§ Cognitive impairment in major depressive disorder > Introduction
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
In the paper
“Individuals who are unemployed are more likely to exhibit decreases in cognitive performance and those who are employed will experience a greater loss of workplace productivity.7”
§ Cognitive impairment in major depressive disorder > Cognition: Implications of Function
What the sources say
- Not checked yetcites [7] source
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“For example, CBT has shown to be effective in treating cognitive symptoms in ADHD, a disorder characterized by significant disturbances in executive function and attention.54”
§ Cognitive impairment in major depressive disorder > Nonpharmacological interventions
What the sources say
- Not checked yetcites [54] source
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“For example, Siegle et al 48 reported that use of the Paced Auditory Serial Addition Test (ie, which requires patients to add sequentially presented digits) increased cognitive skills, decreased maladaptive thoughts (ie, rumination), and improved depressive symptom severity in individuals with MDD.48”
§ Cognitive impairment in major depressive disorder > Nonpharmacological interventions
What the sources say
- Not checked yetcites [48] source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“In one study, although performance on the n-Back test did not differ significantly between MDD subjects and healthy controls, differences were observed in the activation and deactivation of nodal substrates.31”
§ Cognitive impairment in major depressive disorder > Cognition: Neurobiology
What the sources say
- Not checked yetcites [31] source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“Aerobic exercise improves cognition, has negligible side effects, and is scalable (ie, has the potential to be a population-wide health intervention).58”
§ Cognitive impairment in major depressive disorder > Nonpharmacological interventions
What the sources say
- Not checked yetcites [58] source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Abnormalities in the connections between cortical and subcortical structures (ie, prefrontal cortical regions and the ACC) have been hypothesized to lead to poor functional outcomes in MDD.24,30”
§ Cognitive impairment in major depressive disorder > Cognition: Neurobiology
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“Mediators of aberrant neural circuitry, structure, and function are hypothesized to involve imbalances in hormonal regulation (ie, insulin resistance, glucocorticoid abnormalities), neurotrophin dysregulation (ie, brain-derived neurotrophic factor), immunoinflammatory activation, and oxidative stress.[34][35][36][37]”
§ Cognitive impairment in major depressive disorder > Cognition: Neurobiology
What the sources say
- Not checked yetcites [34][35][36][37]
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“Computerized working memory tasks have been shown to improve psychosocial and occupational functioning, as well as hippocampal and frontotemporal activation.50”
§ Cognitive impairment in major depressive disorder > Nonpharmacological interventions
What the sources say
- Not checked yetcites [50] source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“One theory posits that abnormal activity in the medial prefrontal cortex may contribute to the requirement of increased neural effort in individuals with MDD. 31”
§ Cognitive impairment in major depressive disorder > Cognition: Neurobiology
What the sources say
- Not checked yetcites [31] source
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“Infliximab is a promising TNF antagonist that binds to soluble and transmembrane domains of TNF-α, thus preventing the binding of TNF-α to its receptors.74,75”
§ Cognitive impairment in major depressive disorder > Pharmacological interventions
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“Preliminary evidence indicates that liraglutide administered at a dose of 1.8 mg is able to improve depressive and cognitive measures in adults with a depressive mood disorder.72”
§ Cognitive impairment in major depressive disorder > Pharmacological interventions
What the sources say
- Not checked yetcites [72]
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Cognitive deficit is a core domain of depressive psychopathology and a principal mediator of psychosocial and workplace functioning.”
§ Cognitive impairment in major depressive disorder > Conclusion
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
The quote only partly states this claim.
In the paper
“on vortioxetine also showed significant improvements in acquisition time and delayed recall.”
§ Cognitive impairment in major depressive disorder > Pharmacological interventions
What the sources say
- Not checked yetcites [66] source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“While both duloxetine and vortioxetine improved measures of depressive symptom severity, vortioxetine demonstrated a larger direct effect on RAVLT recall and acquisition scores compared to duloxetine.66”
§ Cognitive impairment in major depressive disorder > Pharmacological interventions
What the sources say
- Not checked yetcites [66] source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
The paper relies on this without support.
Cognitive dysfunction is a core diagnostic criterion of major depressive disorder according to the Research Domain Criteria.
“Indeed, cognitive dysfunction is well established as a core diagnostic criterion of MDD according to the Research Domain Criteria (RDoC).”
The paper relies on this without support.
A significant subpopulation of individuals with major depressive disorder does not achieve functional remission after treatment with multiple FDA-approved pharmacological agents.
“A significant subpopulation of individuals with MDD does not achieve functional remission after treatment with multiple FDA-approved pharmacological agents.”
The paper relies on this without support.
Improvements in mood do not necessarily translate into improvements in function.
“It is important to note that improvements in mood do not necessarily translate into improvements in function.”
The paper relies on this without support.
Domain-specific cognitive deficits in learning and memory, executive function, processing speed, and attention and concentration are highly replicated findings in individuals with major depressive disorder presenting with a major depressive episode.
“Domain-specific cognitive deficits in learning and memory, executive function, processing speed, and attention and concentration are highly replicated findings in individuals with MDD presenting with a major depressive episode (MDE).”
The paper relies on this without support.
Individuals with major depressive disorder exhibit a bilateral reduction in hippocampal volume.
“It is recognized that individuals with MDD exhibit a bilateral reduction in hippocampal volume.”
The paper relies on this without support.
The reduction in hippocampal volume is proportional with the frequency of illness episodes.
“The reduction in hippocampal volume has also been shown to be proportional with the frequency of illness episodes.”
The paper relies on this without support.
Individuals with major depressive disorder exhibit hypoactivity of the prefrontal cortex, which is associated with increased activity of the anterior cingulate cortex.
“In addition, individuals with MDD exhibit hypoactivity of the prefrontal cortex, which is associated with increase in activity of the ACC.”
The paper relies on this without support.
Current antidepressant regimens do not primarily target psychosocial impairments and workplace disability in major depressive disorder.
“Despite the foregoing evidence, current antidepressant regimens do not primarily target psychosocial impairments and workplace disability in MDD.”
The paper relies on this without support.
Cognitive disturbances are more commonly observed in individuals with major depressive disorder compared to the general population.
“Cognitive disturbances are more commonly observed in individuals with MDD compared to the general population.”
The paper relies on this without support.
The specific efficacy of computerized measures of cognitive function in clinical populations remains elusive.
“Notwithstanding the foregoing evidence, the specific efficacy of computerized measures of cognitive function in clinical populations remains elusive.”
The paper relies on this without support.
Current psychotherapies primarily target hot cognitive deficits, and effective strategies targeting cold cognition still require further investigation.
“However, current psychotherapies primarily target “hot” cognitive deficits, and therefore effective strategies targeting “cold” cognition still require further investigation.”
The paper relies on this without support.
Brain stimulation therapies are associated with greater tolerability, reduced likelihood of cognitive impairment, and higher rates of remission in treatment-resistant individuals.
“For example, brain stimulation therapies have been associated with greater tolerability, reduced likelihood of cognitive impairment, and higher rates of remission in treatment-resistant individuals.”
The paper relies on this without support.
Available evidence indicates that improvements in measures of cognitive function with conventional antidepressants are associated with improvements in depressive symptom severity.
“Available evidence indicates that improvements in measures of cognitive function with the use of conventional antidepressants are associated with improvements in depressive symptom severity.”
The paper relies on this without support.
There is a paucity of FDA-approved pharmacological agents or interventions that are efficacious, tolerable, and specifically target cognitive dysfunction associated with major depressive disorder.
“There is currently a paucity of FDA-approved pharmacological agents and/or interventions that are efficacious, tolerable, and specifically target cognitive dysfunction associated with MDD.”
The paper relies on this without support.
Incretins may improve cognitive function.
“Preliminary data suggest that incretins may also improve cognitive function.”
The paper relies on this without support.
Intranasal insulin has cognitive-enhancing effects in MDD.
“For example, intranasal insulin has been shown to be procognitive in individuals with MDD.”
The paper relies on this without support.
Intranasal insulin's cognitive benefits are greater in MDD patients who also have diabetes or insulin dysregulation.
“In particular, the procognitive effects of intranasal insulin are stronger in individuals with a history of diabetes and insulin dysregulation comorbid with MDD.”
The authors state this as an assumption.
TNF-α antagonists are an effective add-on for cognitive symptoms in MDD.
“Treatment with TNF-α antagonists is postulated to be an efficacious adjunctive approach to target cognitive symptoms in individuals with MDD.”
The paper relies on this without support.
In the brain, insulin blocks proapoptotic pathways and is important for neuroplasticity, neurogenesis, and neuronal growth and survival.
“In the brain, insulin inhibits proapoptotic pathways and plays critical roles in neuroplasticity, neurogenesis, and neuronal growth and survival.”
The paper relies on this without support.
Psychostimulants are prescribed for depressive symptoms in MDD.
“Psychostimulants have also been used to treat depressive symptoms in individuals with MDD; however, available evidence is mixed.”
The paper relies on this without support.
Available evidence on psychostimulants for depressive symptoms in MDD is mixed.
“Psychostimulants have also been used to treat depressive symptoms in individuals with MDD; however, available evidence is mixed.”
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In the citing paper
“BDNF can indeed cross the barrier in mice [110].”
From Variations in BDNF and Their Role in the Neurotrophic Antidepressant Mechanisms of Ketamine and Esketamine: A Review (2024) · cites this paper as [110]
Experimental — accuracy not yet measured
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Metadata
- Authors
- Pan, Z., Park, C., Brietzke, E., Zuckerman, H., Rong, C., Mansur, R. B., Fus, D., Subramaniapillai, M., Lee, Y., & McIntyre, R. S.
- Affiliations
- University Health Network (CA)
- Corresponding author
- McIntyre, Roger S.
- ORCID
- Venue
- CNS Spectrums
- Publisher
- Cambridge University Press (CUP)
- Published
- 2018-11-23
- Volume
- 24
- Issue
- 1
- Pages
- 22-29
- ISSN
- 1092-8529 (ISSN-L)
- 2165-6509
- OpenAlex
- W2901954088
- Semantic Scholar
- 3ed10b2aa1187ce71f325187e67ab657165d7191
- Cited by
- 320
- References
- 79
- Citations by year
- 2026: 50 · 2025: 65 · 2024: 80 · 2023: 52 · 2022: 37 · 2021: 26 · 2020: 5 · 2019: 4 · 2018: 1
- FWCI
- 1.05
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- CNS Spectrums (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Pharmacology (medical) › Treatment of Major Depression
- Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
- Life Sciences › Neuroscience › Cognitive Neuroscience › Neural and Behavioral Psychology Studies
- Keywords
- major depressive disorder, cognitive impairment, learning and memory, executive function, processing speed, attention, antidepressants, neuroinflammation, neurobiological mechanisms, psychosocial functioning, quality of life, treatment goals
- MeSH terms
- Antidepressive Agents, Cognition, Cognition Disorders, Major Depressive Disorder, Depressive Disorder, Major, Humans, Nootropic Agents
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