Combined Cognitive Training and Vortioxetine Mitigates Age-Related Declines in Functional Brain Network Integrity

Published:January 13, 2023DOI:


      • What is the primary question addressed by this study?The primary question addressed was whether adding a pro-cognitive medication (vortioxetine) to cognitive training would alter the association of aging with changes in resting state brain networks across a 6-month trial period.
      • What is the main finding of this study?Vortioxetine added to computerized cognitive training produced significantly greater changes in older adult brain network organization than cognitive training alone over 6 months. Discrete intervention group effects were most evident in the interactions of aging with longitudinal changes in whole brain network segregation and with cingulo-opercular network strength.
      • What is the meaning of the finding?For older adults experiencing age-related cognitive decline, adding vortioxetine to intensive cognitive training has a potentially beneficial effect on the correspondence between aging and functional brain network organization.



      Age-related cognitive decline is common and potentially modifiable with cognitive training. Combining cognitive training with pro-cognitive medication offers an opportunity to modify brain networks to mitigate age-related cognitive decline. We tested the hypothesis that the efficacy of cognitive training could be amplified by combining it with vortioxetine, a pro-cognitive and pro-neuroplastic multimodal antidepressant.


      We evaluated the effects of 6 months of computerized cognitive training plus vortioxetine (versus placebo) on resting state functional connectivity in older adults (age 65+) with age-related cognitive decline. We first evaluated the association of functional connectivity with age and cognitive performance (N = 66). Then we compared the effects of vortioxetine plus cognitive training versus placebo plus cognitive training on connectivity changes over the training period (n = 20).


      At baseline, greater age was significantly associated with lower within-network strength and network segregation, and poorer cognitive function. Cognitive training plus vortioxetine over 6 months positively impacted the relationship between age to mean network segregation. These effects were not observed in the placebo group. In contrast, vortioxetine did not modify the relationship of age to change in mean within-network strength. Exploratory analyses identified the cingulo-opercular network as the network most affected by cognitive training plus vortioxetine.


      This preliminary study provides evidence that combining cognitive training with pro-cognitive medication may modulate the effects of aging on functional brain networks. Results indicate that for older adults experiencing age-related cognitive decline, vortioxetine has a potentially beneficial effect on the correspondence between aging and functional brain network segregation. These results await replication in a larger sample.


      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to The American Journal of Geriatric Psychiatry
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Park DC
        • Lautenschlager G
        • Hedden T
        • et al.
        Models of visuospatial and verbal memory across the adult life span.
        Psychol Aging. 2002; 17: 299-320
        • Boyle PA
        • Wilson RS
        • Yu L
        • et al.
        Much of late life cognitive decline is not due to common neurodegenerative pathologies.
        Ann Neurol. 2013; 74: 478-489
        • Stern Y
        • Arenaza-Urquijo EM
        • Bartrés-Faz D
        • et al.
        Whitepaper: defining and investigating cognitive reserve, brain reserve, and brain maintenance.
        Alzheimer's & Dementia. 2020; 16: 1305-1311
        • Lustig C
        • Shah P
        • Seidler R
        • et al.
        Aging, training, and the brain: a review and future directions.
        Neuropsychol Rev. 2009; 19: 504-522
        • Lampit A
        • Hallock H
        • Valenzuela M
        Computerized cognitive training in cognitively healthy older adults: a systematic review and meta-analysis of effect modifiers.
        PLoS Med. 2014; 11e1001756
        • Lenze EJ
        • Stevens A
        • Waring JD
        • et al.
        Augmenting computerized cognitive training with vortioxetine for age-related cognitive decline: a randomized controlled trial.
        Am J Psychiatry. 2020; 177: 548-555
        • De Diego-Adeliño J
        • Crespo JM
        • Mora F
        • et al.
        Vortioxetine in major depressive disorder: from mechanisms of action to clinical studies. An updated review.
        Expert Opin Drug Saf. 2022; 21: 673-690
        • Katona C
        • Hansen T
        • Olsen CK
        A randomized, double-blind, placebo-controlled, duloxetine-referenced, fixed-dose study comparing the efficacy and safety of Lu AA21004 in elderly patients with major depressive disorder.
        Int Clin Psychopharmacol. 2012; 27: 215-223
        • Mahableshwarkar AR
        • Zajecka J
        • Jacobson W
        • et al.
        A randomized, placebo-controlled, active-reference, double-blind, flexible-dose study of the efficacy of vortioxetine on cognitive function in major depressive disorder.
        Neuropsychopharmacology. 2015; 40: 2025-2037
        • McIntyre RS
        • Florea I
        • Tonnoir B
        • et al.
        Efficacy of vortioxetine on cognitive functioning in working patients with major depressive disorder.
        J Clin Psychiatry. 2017; 78: 115-121
        • Dale E
        • Zhang H
        • Leiser SC
        • et al.
        Vortioxetine disinhibits pyramidal cell function and enhances synaptic plasticity in the rat hippocampus.
        J Psychopharmacol. 2014; 28: 891-902
        • Sanchez C
        • Asin KE
        • Artigas F
        Vortioxetine, a novel antidepressant with multimodal activity: review of preclinical and clinical data.
        Pharmacol Ther. 2015; 145: 43-57
        • Chen F
        • du Jardin KG
        • Waller JA
        • et al.
        Vortioxetine promotes early changes in dendritic morphology compared to fluoxetine in rat hippocampus.
        Eur Neuropsychopharmacol. 2016; 26: 234-245
        • Ferreira LK
        • Busatto GF
        Resting-state functional connectivity in normal brain aging.
        Neurosci Biobehav Rev. 2013; 37: 384-400
        • Fox MD
        • Snyder AZ
        • Vincent JL
        • et al.
        The human brain is intrinsically organized into dynamic, anticorrelated functional networks.
        Proc Natl Acad Sci USA. 2005; 102: 9673-9678
        • Hacker CD
        • Laumann TO
        • Szrama NP
        • et al.
        Resting state network estimation in individual subjects.
        Neuroimage. 2013; 82: 616-633
        • Power JD
        • Cohen AL
        • Nelson SM
        • et al.
        Functional network organization of the human brain.
        Neuron. 2011; 72: 665-678
        • Seitzman BA
        • Gratton C
        • Marek S
        • et al.
        A set of functionally-defined brain regions with improved representation of the subcortex and cerebellum.
        NeuroImage. 2020; 206116290
        • Chan MY
        • Park DC
        • Savalia NK
        • et al.
        Decreased segregation of brain systems across the healthy adult lifespan.
        Proc Natl Acad Sci USA. 2014; 111: E4997-E5006
        • Cohen JR
        • D'Esposito M
        The segregation and integration of distinct brain networks and their relationship to cognition.
        J Neurosci. 2016; 36: 12083-12094
        • Ewers M
        • Luan Y
        • Frontzkowski L
        • et al.
        Segregation of functional networks is associated with cognitive resilience in Alzheimer's disease.
        Brain. 2021; 144: 2176-2185
        • Brier MR
        • Thomas JB
        • Snyder AZ
        • et al.
        Loss of intranetwork and internetwork resting state functional connections with Alzheimer's disease progression.
        J Neurosci. 2012; 32: 8890-8899
        • Damoiseaux JS.
        Effects of aging on functional and structural brain connectivity.
        NeuroImage. 2017; 160: 32-40
        • Spreng RN
        • Stevens WD
        • Viviano JD
        • et al.
        Attenuated anticorrelation between the default and dorsal attention networks with aging: evidence from task and rest.
        Neurobiol Aging. 2016; 45: 149-160
        • Smith J
        • Browning M
        • Conen S
        • et al.
        Vortioxetine reduces BOLD signal during performance of the N-back working memory task: a randomised neuroimaging trial in remitted depressed patients and healthy controls.
        Mol Psychiatry. 2018; 23: 1127-1133
        • Xiong S
        • Li W
        • Zhou Y
        • et al.
        Vortioxetine modulates the regional signal in first-episode drug-free major depressive disorder at rest.
        Front Psychiatry. 2022; 13950885
        • Heaton RK
        • Akshoomoff N
        • Tulsky D
        • et al.
        Reliability and validity of composite scores from the NIH Toolbox Cognition Battery in adults.
        J Int Neuropsychol Soc. 2014; 20: 588-598
        • First M
        • Williams J
        • Karg R
        • et al.
        Structured Clinical Interview for DSM-5.
        American Psychiatric Assocation, Washington, DC2015
        • Kroenke K
        • Spitzer RL
        • Williams JB
        The PHQ-9: validity of a brief depression severity measure.
        J Gen Intern Med. 2001; 16: 606-613
        • Crittendon J
        • Hopko DR
        Assessing worry in older and younger adults: psychometric properties of an abbreviated Penn State Worry Questionnaire (PSWQ-A).
        J Anxiety Disord. 2006; 20: 1036-1054
        • Folstein M
        • Folstein S
        • McHugh P
        A practical method for grading the cognitive state of patients for the clinician.
        J Psychiatr Res. 1975; 12: 189-198
        • Bowie CR
        • McGurk SR
        • Mausbach B
        • et al.
        Combined cognitive remediation and functional skills training for schizophrenia: effects on cognition, functional competence, and real-world behavior.
        AJP. 2012; 169: 710-718
        • Bowie CR
        • Gupta M
        • Holshausen K
        • et al.
        Cognitive remediation for treatment-resistant depression: effects on cognition and functioning and the role of online homework.
        J Nerv Ment Dis. 2013; 201: 680-685
        • Raut RV
        • Mitra A
        • Snyder AZ
        • et al.
        On time delay estimation and sampling error in resting-state fMRI.
        NeuroImage. 2019; 194: 211-227
        • Snyder AZ
        • Nishino T
        • Shimony JS
        • et al.
        Covariance and correlation analysis of resting state functional magnetic resonance imaging data acquired in a clinical trial of mindfulness-based stress reduction and exercise in older individuals.
        Front Neurosci. 2022; 16825547
        • Power JD
        • Barnes KA
        • Snyder AZ
        • et al.
        Spurious but systematic correlations in functional connectivity MRI networks arise from subject motion.
        NeuroImage. 2012; 59: 2142-2154
        • Power JD
        • Mitra A
        • Laumann TO
        • et al.
        Methods to detect, characterize, and remove motion artifact in resting state fMRI.
        NeuroImage. 2014; 84: 320-341
        • Meeker KL
        • Ances BM
        • Gordon BA
        • et al.
        Cerebrospinal fluid Aβ42 moderates the relationship between brain functional network dynamics and cognitive intraindividual variability.
        Neurobiol Aging. 2021; 98: 116-123
        • Sala-Llonch R
        • Junqué C
        • Arenaza-Urquijo EM
        • et al.
        Changes in whole-brain functional networks and memory performance in aging.
        Neurobiol Aging. 2014; 35: 2193-2202
        • Thomas JB
        • Brier MR
        • Snyder AZ
        • et al.
        Pathways to neurodegeneration: effects of HIV and aging on resting-state functional connectivity.
        Neurology. 2013; 80: 1186-1193
        • Hausman HK
        • O'Shea A
        • Kraft JN
        • et al.
        The role of resting-state network functional connectivity in cognitive aging.
        Front Aging Neurosci. 2020; 12: 177
        • Contreras JA
        • Avena-Koenigsberger A
        • Risacher SL
        • et al.
        Resting state network modularity along the prodromal late onset Alzheimer's disease continuum.
        NeuroImage: Clinical. 2019; 22101687
        • Birn RM
        • Molloy EK
        • Patriat R
        • et al.
        The effect of scan length on the reliability of resting-state fMRI connectivity estimates.
        NeuroImage. 2013; 83: 550-558

      Linked Article

      • Augmentation of cognitive training with vortioxetine opens new avenues for targeting age-related changes in brain connectivity
        The American Journal of Geriatric Psychiatry
        • Preview
          With a rapidly aging population, there has been great interest in using cognitive training to enhance cognitive function in older adults and age-related diseases. Studies evaluating cognitive enhancing interventions demonstrate mixed findings on efficacy. Effect sizes are heterogenous across studies and there is inconsistent evidence of transfer to improvements in everyday cognitive tasks. To develop more effective treatments, clinical researchers have increasingly turned to interventions that combine approaches (e.g., computerized cognitive training, exercise, neuromodulation) and that attempt to target circuit-specific mechanisms of cognitive dysfunction [1].
        • Full-Text
        • PDF