Cognitive dysfunction in major depression: From assessment to novel therapies

Atique-Ur-Rehman, Hafsa; Neill, Joanna C.

doi:10.1016/j.pharmthera.2019.05.013

Cited by 73Treatment of Major DepressionAnxiety, Depression, Psychometrics, Treatment, Cognitive ProcessesDementia and Cognitive Impairment Research

Cognitive dysfunction in major depression: From assessment to novel therapies

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Atique-Ur-Rehman, Hafsa, Neill, Joanna C.·2019·Pharmacology & Therapeutics

DOI 10.1016/j.pharmthera.2019.05.013

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Abstract

Major depressive disorder (MDD) is a disabling disease associated with profound functional impairment. Cognitive deficits, increasingly recognised as a core feature of MDD, reduce educational, occupational and social outcomes, and impair quality of life and functionality. Unlike cognitive impairments associated with schizophrenia (CIAS), cognitive impairments in depression have been under diagnosed and are poorly understood. Consensus has yet to be reached regarding the nature of these deficits, their appropriate assessment and treatment options. It is unclear whether existing treatments have an impact on cognitive deficits. Here, we conduct a thorough and extensive review of recent published work on this unmet clinical need (2014-2018). We evaluate the validity of available assessment tools, and examine the evidence for efficacy of current and novel pharmacological therapies. From our analysis, we have established that cognitive deficits are indeed widespread in MDD patients. The THINC-it tool, a recently validated and sensitive cognitive assessment instrument, shows promise for earlier detection of cognitive impairment associated with MDD and could easily be applied in clinical practice. Several potential novel therapies are emerging. Methodological inconsistencies and small underpowered studies, however, have led to conflicting results and inconclusive evidence. Our recommendations include: development of a standardised neurocognitive test battery for MDD, improving clinical trial design, investigating sex differences, and patient stratification. These changes should support the development of improved therapeutic strategies for cognitive dysfunction in MDD patients, as well as facilitate their use in clinical practice.

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Cognitive impairment as measured by the THINC-integrated tool (THINC-it): Association with psychosocial function in major depressive disorder
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Effects of omega-3 fatty acid supplementation on mood and emotional information processing in recovered depressed individuals
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The effect of erythropoietin on cognition in affective disorders – Associations with baseline deficits and change in subjective cognitive complaints
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Depressive disorders: Processes leading to neurogeneration and potential novel treatments
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Erythropoietin modulates neural and cognitive processing of emotional information in biomarker models of antidepressant drug action in depressed patients
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Vortioxetina: una nueva alternativa en el trastorno depresivo mayor
Salagre, E., Grande, I., Solé, B., Sánchez‐Moreno, J., & Vieta, E. (2017) · Revista de Psiquiatría y Salud Mental · doi:10.1016/j.rpsm.2017.06.006 · Cited by 40 · see citing works
Cognitive predictors of illness course at 12 months after first-episode of depression
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Enhanced theta-gamma coupling associated with hippocampal volume increase following high-frequency left prefrontal repetitive transcranial magnetic stimulation in patients with major depression
Noda, Y., Zomorrodi, R., Daskalakis, Z. J., Blumberger, D. M., & Nakamura, M. (2018) · International Journal of Psychophysiology · doi:10.1016/j.ijpsycho.2018.07.004 · Cited by 40 · see citing works
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Adjunctive S-adenosylmethionine (SAMe) in treating non-remittent major depressive disorder: An 8-week double-blind, randomized, controlled trial,
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Venlafaxine treatment reduces the deficit of executive control of attention in patients with major depressive disorder
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Neural and Behavioral Predictors of Treatment Efficacy on Mood Symptoms and Cognition in Mood Disorders: A Systematic Review
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The lack of meaningful association between depression severity measures and neurocognitive performance
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Cognitive Impairment Along the Course of Depression: Non-Pharmacological Treatment Options
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Longitudinal associations between biomarkers of inflammation and changes in depressive symptoms in patients with type 1 and type 2 diabetes
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A Double-Blind, Randomized, 26-Week Study Comparing the Cognitive and Psychomotor Effects and Efficacy of 75 mg (37.5 mg b.i.d.) Venlafaxine and 75 mg (25 mg Mane, 50 mg Nocte) Dothiepin in Elderly Patients with Moderate Major Depression Being Treated in General Practice
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Cognition in depression: Can we THINC-it better?
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Changes in cognitive symptoms after a buspirone–melatonin combination treatment for Major Depressive Disorder
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Cognitive outcome after ventral capsule/ventral striatum stimulation for treatment-resistant major depression
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Vortioxetine: A new alternative for the treatment of major depressive disorder
Salagre, E., Grande, I., Solé, B., Sánchez‐Moreno, J., & Vieta, E. (2018) · Revista de Psiquiatría y Salud Mental (English Edition) · doi:10.1016/j.rpsmen.2018.02.005 · Cited by 28 · see citing works
Erythropoietin for Cognitive Deficits Associated with Schizophrenia, Bipolar Disorder, and Major Depression: A Systematic Review
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The impact of cognitive challenges in major depression: the role of the primary care physician
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Evaluation of the benefits of exercise on cognition in major depressive disorder
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Executive Subdomains Are Differentially Associated With Psychosocial Outcomes in Major Depressive Disorder
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The effect of desvenlafaxine on cognitive functioning in employed outpatients with major depressive disorder: a substudy of a randomized, double-blind, placebo-controlled trial
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A randomized, double-blind, placebo-controlled, dose-ranging study of lisdexamfetamine dimesylate augmentation for major depressive disorder in adults with inadequate response to antidepressant therapy
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Long-term consequences of COVID-19 on cognitive functioning up to 6 months after discharge: role of depression and impact on quality of life
Poletti, S., Palladini, M., Mazza, M. G., LORENZO, R. D., Bollettini, I., Sara, B., Bravi, B., Ceciclio, B., Stefania, C., Valentina, C., et al. (2021) · European Archives of Psychiatry and Clinical Neuroscience · doi:10.1007/s00406-021-01346-9 · Cited by 136 · see citing works
Salidroside Ameliorates Depression by Suppressing NLRP3-Mediated Pyroptosis via P2X7/NF-κB/NLRP3 Signaling Pathway
Chai, Y., Cai, Y., Fu, Y., Wang, Y., Zhang, Y., Zhang, X., Zhu, L., Miao, M., & Yan, T. (2022) · Frontiers in Pharmacology · doi:10.3389/fphar.2022.812362 · Cited by 100 · see citing works
An Update of Palmitoylethanolamide and Luteolin Effects in Preclinical and Clinical Studies of Neuroinflammatory Events
Cordaro, M., Cuzzocrea, S., & Crupi, R. (2020) · Antioxidants · doi:10.3390/antiox9030216 · Cited by 98 · see citing works
Low Doses of Psilocybin and Ketamine Enhance Motivation and Attention in Poor Performing Rats: Evidence for an Antidepressant Property
Higgins, G. A., Carroll, N. K., Brown, M., MacMillan, C., Silenieks, L. B., Thevarkunnel, S., Izhakova, J., Magomedova, L., DeLannoy, I., & Sellers, E. M. (2021) · Frontiers in Pharmacology · doi:10.3389/fphar.2021.640241 · Cited by 70 · see citing works
Inhibition of phosphodiesterase-4 suppresses HMGB1/RAGE signaling pathway and NLRP3 inflammasome activation in mice exposed to chronic unpredictable mild stress
Xie, J., Bi, B., Qin, Y., Dong, W., Zhong, J., Li, M., Cheng, Y., Xu, J., & Wang, H. (2020) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2020.11.029 · Cited by 61 · see citing works
Mechanisms of Cognitive Impairment in Depression. May Probiotics Help?
Dobielska, M., Bartosik, N. K., Zyzik, K. A., Kowalczyk, E., & Karbownik, M. S. (2022) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2022.904426 · Cited by 54 · see citing works
The association between persistent cognitive difficulties and depression and functional outcomes in people with major depressive disorder
Matcham, F., Simblett, S. K., Leightley, D., Dalby, M., Siddi, S., Haro, J. M., Lamers, F., Penninx, B. W. J. H., Bruce, S., Nica, R. I., et al. (2022) · Psychological Medicine · doi:10.1017/s0033291722003671 · Cited by 43 · see citing works
Change in Cognitive Function over the Course of Major Depressive Disorder: A Systematic Review and Meta-analysis
Ahern, E., White, J., & Slattery, E. J. (2024) · Neuropsychology Review · doi:10.1007/s11065-023-09629-9 · Cited by 41 · see citing works
Quercetin Ameliorates Cognitive Impairment in Depression by Targeting HSP90 to Inhibit NLRP3 Inflammasome Activation
Du, L., Fan, X., Yang, Y., Wu, S., & Liu, Y. (2024) · Molecular Neurobiology · doi:10.1007/s12035-024-03926-x · Cited by 39 · see citing works
The causal involvement of the BDNF-TrkB pathway in dentate gyrus in early-life stress-induced cognitive deficits in male mice
Sun, Y., Su, Y., Wang, Q., Zheng, J.-Y., Zhang, C., Wang, T., Liu, X., Ma, Y., Li, X., Zhang, X., et al. (2023) · Translational Psychiatry · doi:10.1038/s41398-023-02476-5 · Cited by 38 · see citing works
Taurine Alleviates Chronic Social Defeat Stress-Induced Depression by Protecting Cortical Neurons from Dendritic Spine Loss
Zhu, Y., Wang, R., Fan, Z., Luo, D., Cai, G., Li, X., Han, J., Zhuo, L., Zhang, L., Zhang, H., et al. (2022) · Cellular and Molecular Neurobiology · doi:10.1007/s10571-022-01218-3 · Cited by 35 · see citing works
Schisandrol B alleviates depression-like behavior in mice by regulating bile acid homeostasis in the brain-liver-gut axis via the pregnane X receptor
Wang, P., Ouyang, H., Bi, G., Liang, F., Wu, C., Wu, C., Jiang, X., Zhou, W., Li, D., Zhang, S., et al. (2024) · Phytomedicine · doi:10.1016/j.phymed.2024.156340 · Cited by 33 · see citing works
fNIRS Evaluation of Frontal and Temporal Cortex Activation by Verbal Fluency Task and High-Level Cognition Task for Detecting Anxiety and Depression
Lang, X., Wen, D., Li, Q., Yin, Q., Wang, M., & Xu, Y. J. (2021) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2021.690121 · Cited by 31 · see citing works
Connectivity of the Frontal Cortical Oscillatory Dynamics Underlying Inhibitory Control During a Go/No-Go Task as a Predictive Biomarker in Major Depression
Han, Y., Dai, Z., Chattun, M. R., Lin, P., Zhou, H., Wang, H.-F., Yao, Z., & Lü, Q. (2020) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2020.00707 · Cited by 28 · see citing works
L-Carnitine in the Treatment of Psychiatric and Neurological Manifestations: A Systematic Review
Wang, W., Pan, D., Liu, Q., Chen, X., & Wang, S. (2024) · Nutrients · doi:10.3390/nu16081232 · Cited by 27 · see citing works
Purinergic transmission in depressive disorders
Szopa, A., Socała, K., Serefko, A., Doboszewska, U., Wróbel, A., Poleszak, E., & Właź, P. (2021) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2021.107821 · Cited by 25 · see citing works
Motor cortical plasticity as a predictor of treatment response to high frequency repetitive transcranial magnetic stimulation (rTMS) for cognitive function in drug-naive patients with major depressive disorder
Li, X., Yu, C., Ding, Y., Chen, Z., Zhuang, W., Liu, Z., Fan, J., Yan, H., Xu, W., Zhu, G., et al. (2023) · Journal of Affective Disorders · doi:10.1016/j.jad.2023.04.085 · Cited by 25 · see citing works
Natural product Kaji-ichigoside F1 exhibits rapid antidepression via activating the AMPA–BDNF–mTOR pathway and inhibiting the NMDAR–CaMKIIα pathway
Chen, F., Li, L., Huang, M., Wang, Y., Wang, L., Jin, F., Yang, L., Gao, M., Li, L., Wang, Y., et al. (2024) · Phytomedicine · doi:10.1016/j.phymed.2024.155452 · Cited by 22 · see citing works
Antidepressant and anti-amnesic effects of the aqueous lyophilisate of the leaves of Leptadenia arborea on an animal model of cognitive deficit associated depression
Ngoupaye, G. T., Yassi, F. B., Bahane, D. A. N., Pahaye, D. B., & Bum, E. N. (2020) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2020.110603 · Cited by 22 · see citing works
Metabolic Syndrome and Cardiovascular Disease Impacts on the Pathophysiology and Phenotype of HIV-Associated Neurocognitive Disorders
Moulignier, A., & Costagliola, D. G. (2020) · Current topics in behavioral neurosciences · doi:10.1007/7854_2019_123 · Cited by 22 · see citing works
Reliability and Validity of THINC-it in Evaluating Cognitive Function of Patients with Bipolar Depression
Zhang, W., Zhu, N., Lai, J., Liu, J., Ng, C. H., Chen, J., Qian, C., Du, Y., Hu, C., Chen, J., et al. (2020) · Neuropsychiatric Disease and Treatment · doi:10.2147/ndt.s266642 · Cited by 20 · see citing works
The Effects of Tai Chi on the Executive Functions and Physical Fitness in Middle-Aged Adults with Depression: A Randomized Controlled Trial
Zhang, L., Wang, D., Xie, C., Liu, S., Chi, L., Ma, X., & Ren, F.-F. (2022) · Evidence-based Complementary and Alternative Medicine · doi:10.1155/2022/1589106 · Cited by 20 · see citing works
Diet and Neurocognition in Mood Disorders - An Overview of the Overlooked
Balanzá‐Martínez, V., Shansis, F., Tatay-Manteiga, A., & López-García, P. (2020) · Current Pharmaceutical Design · doi:10.2174/1381612826666200318152530 · Cited by 18 · see citing works
Task and Non-task Brain Activation Differences for Assessment of Depression and Anxiety by fNIRS
Wen, D., Lang, X., Zhang, H., Li, Q., Yin, Q., Chen, Y., & Xu, Y. J. (2021) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2021.758092 · Cited by 16 · see citing works
Exploring the Potential of Probiotics and Prebiotics in Major Depression: From Molecular Function to Clinical Therapy
Yuan, X., Chai, J., Xu, W., & Zhao, Y. (2024) · Probiotics and Antimicrobial Proteins · doi:10.1007/s12602-024-10326-z · Cited by 15 · see citing works
The Effect of Cognitive Impairment on the Prognosis of Major Depressive Disorder
Zhang, B., Feng, L., Feng, Y., Xin, L.-M., Zhu, X., Tan, Y., & Wang, G. (2020) · The Journal of Nervous and Mental Disease · doi:10.1097/nmd.0000000000001180 · Cited by 15 · see citing works
Targeting the dysfunction of glutamate receptors for the development of novel antidepressants
Xia, C., He, J., Du, L., Yan, Y., Lian, W., Xu, J., & Zhang, W. (2021) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2021.107875 · Cited by 14 · see citing works
A multiple-step screening protocol to identify norepinephrine and dopamine reuptake inhibitors for depression
Wang, P., Yan, F., Dong, J., Wang, S., Shi, Y., Zhu, M., Zuo, Y., Ma, H., Xue, R., Zhai, D., et al. (2023) · Physical Chemistry Chemical Physics · doi:10.1039/d2cp05676c · Cited by 14 · see citing works
Effectiveness, tolerability, and dropout rates of vortioxetine in comorbid depression: A naturalistic study
Carlo, V. D., Vismara, M. E. M., Grancini, B. M., Benatti, B., Bosi, M. F., Colombo, A., Viganò, C. A., & Dell’Osso, B. M. (2020) · Human Psychopharmacology Clinical and Experimental · doi:10.1002/hup.2750 · Cited by 14 · see citing works
Intrinsic Organization of Occipital Hubs Predicts Depression: A Resting-State fNIRS Study
Xu, Y., Wang, Y., Hu, N., Yang, L., Yu, Z., Li, H., Xu, Q., Zhou, J., Ji, C., Mao, H., et al. (2022) · Brain Sciences · doi:10.3390/brainsci12111562 · Cited by 13 · see citing works
Inflammatory Markers and Episodic Memory Functioning in Depressive Disorders
Wachowska, K., Szemraj, J., Śmigielski, J., & Gałecki, P. (2022) · Journal of Clinical Medicine · doi:10.3390/jcm11030693 · Cited by 13 · see citing works
Depression among Patients with an Implanted Left Ventricular Assist Device: Uncovering Pathophysiological Mechanisms and Implications for Patient Care
Alnsasra, H., Khalil, F. M., Perue, R. K., & Azab, A. N. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms241411270 · Cited by 11 · see citing works
Cardiopulmonary rehabilitation’s influence on cognitive functions, psychological state, and sleep quality in long COVID-19 patients: A randomized controlled trial
Gaudreau-Majeau, F., Gagnon, C., Clavet, S., Bérubé, B., Malo, J., Iglesies‐Grau, J., Gayda, M., Bherer, L., & Besnier, F. (2024) · Neuropsychological Rehabilitation · doi:10.1080/09602011.2024.2338613 · Cited by 10 · see citing works
Serum homocysteine showed potential association with cognition and abnormal gut microbiome in major depressive disorder
Xu, C., Zhao, W.-X., Yu, S., Yun, Y., Ma, T., Fan, N., Song, J., Wang, J., & Zhang, Q. (2025) · World Journal of Psychiatry · doi:10.5498/wjp.v15.i3.102567 · Cited by 10 · see citing works
Mechanisms of the effect of gut microbes on depression through the microbiota-gut-brain axis
Zhou, X., Wang, S., Wang, X., Chen, X., Zhou, P., Ma, K., & Zhang, P. (2025) · Frontiers in Nutrition · doi:10.3389/fnut.2025.1634548 · Cited by 13 · see citing works
Altered brain regional homogeneity, depressive symptoms, and cognitive impairments in medication-free female patients with current depressive episodes in bipolar disorder and major depressive disorder
Ni, S., Peng, T., Gao, S., Ling, C., Wu, F., Jiang, J., Sun, J., Xiao, C., & Xu, X. (2024) · BMC Psychiatry · doi:10.1186/s12888-024-06352-4 · Cited by 9 · see citing works
Association between cognitive impairments and aberrant dynamism of overlapping brain sub-networks in unmedicated major depressive disorder: A resting-state MEG study
Zhong, S., Chen, N., Lai, S., Shan, Y., Li, Z., Chen, J., Luo, A., Zhang, Y., Lv, S., He, J., et al. (2022) · Journal of Affective Disorders · doi:10.1016/j.jad.2022.09.069 · Cited by 9 · see citing works
Association of adolescent self-esteem in 2014 and cognitive performance in 2014, 2016, and 2018: a longitudinal study
Wang, X., Liu, Y., Zhao, Z., Liu, W., Chen, Y., Chen, Y., & Zang, S. (2023) · Frontiers in Psychology · doi:10.3389/fpsyg.2023.1180397 · Cited by 11 · see citing works
Dried Loquat Fruit Extract Containing Chlorogenic Acid Prevents Depressive-like Behaviors Induced by Repeated Corticosteroid Injections in Mice
Lim, D. W., Yoo, G., & Lee, C.-H. (2023) · Molecules · doi:10.3390/molecules28145612 · Cited by 9 · see citing works
Oxidative stress and cognitive function in Chinese patients with major depressive disorder: the mediating role of depression severity
Peng, R., Sun, C., Fan, Y., Li, J., Gao, J., Sun, W.-X., Zhang, X.-B., & Tian, Q. (2025) · BMC Psychiatry · doi:10.1186/s12888-025-07478-9 · Cited by 7 · see citing works
Clinical Quest for Associated Cognitive Impairment in Major Depressed Patients
Suciu, B. D., & Micluția, I. (2020) · Psychiatric Quarterly · doi:10.1007/s11126-020-09733-6 · Cited by 8 · see citing works
Assessment of cognitive performances in major depressed patients: a 6-month follow-up study
Suciu, B. D., Paunescu, R., & Micluția, I. (2020) · International Journal of Psychiatry in Clinical Practice · doi:10.1080/13651501.2020.1840595 · Cited by 6 · see citing works
Relationship of insight to neurocognitive function and risk of recurrence in depression: A naturalistic follow-up study
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Authors: Atique-Ur-Rehman, H., & Neill, J. C.
Affiliations: Manchester University NHS Foundation Trust (GB)
University of Manchester (GB)
Corresponding author: Neill, Joanna C.
ORCID: Neill, Joanna C.
Venue: Pharmacology & Therapeutics
Publisher: Elsevier BV
Published: 2019-10
Volume: 202
Pages: 53-71
ISSN: 0163-7258 (ISSN-L)
DOI: 10.1016/j.pharmthera.2019.05.013
OpenAlex: W2948108171
Cited by: 72
References: 105
Citations by year: 2026: 10 · 2025: 9 · 2024: 13 · 2023: 9 · 2022: 13 · 2021: 6 · 2020: 12
FWCI: 0.99
Type: journal article
Language: en
Open access: green
research.manchester.ac.uk
Licence: other-oa
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/legal/tdmrep-license (tdm)
Locations: Pharmacology & Therapeutics (publishedVersion)
PubMed (publishedVersion)
Research Explorer (The University of Manchester) (submittedVersion, other-oa)
Topics: Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
Social Sciences › Psychology › Experimental and Cognitive Psychology › Anxiety, Depression, Psychometrics, Treatment, Cognitive Processes
Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
Keywords: major depressive disorder, cognitive impairment, cognitive assessment tools, pharmacotherapy, new drugs, sex differences, patient stratification, clinical trial design, quality of life
MeSH terms: Mental Status and Dementia Tests, Animals, Major Depressive Disorder, Humans, Sex Characteristics, Cognitive Dysfunction

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