Cognitive impairment in depression: recent advances and novel treatments

Giulia Perini, Matteo Cotta Ramusino, Elena Sinforiani, Sara Bernini, Roberto Petrachi, Alfredo Costa, Giulia Perini, Matteo Cotta Ramusino, Elena Sinforiani, Sara Bernini, Roberto Petrachi, Alfredo Costa

Abstract

In the past, little or no attention was paid to cognitive disorders associated with depression (a condition sometimes termed pseudodementia). However, recent years have seen a growing interest in these changes, not only because of their high frequency in acute-stage depression, but also because they have been found to persist, as residual symptoms (in addition to affective and psychomotor ones), in many patients who respond well to antidepressant treatment. These cognitive symptoms seem to impact significantly not only on patients' functioning and quality of life, but also on the risk of recurrence of depression. Therefore, over the past decade, pharmacological research in this field has focused on the development of new agents able to counteract not only depressive symptoms, but also cognitive and functional ones. In this context, novel antidepressants with multimodal activity have emerged. This review considers the different issues, in terms of disease evolution, raised by the presence of cognitive disorders associated with depression and considers, particularly from the neurologist's perspective, the ways in which the clinical approach to cognitive symptoms, and their interpretation to diagnostic and therapeutic ends, have changed in recent years. Finally, after outlining the pharmacodynamics and pharmacokinetics of the first multimodal antidepressant, vortioxetine, it reports the main results obtained with the drug in depressed patients, also in consideration of the ever-increasing evidence on its different mechanisms of action in animal models.

Keywords: SSRIs; antidepressant drugs; depression; major depressive disorder; pseudodementia; vortioxetine.

Conflict of interest statement

The authors report no conflicts of interest in this work.

Figures

Figure 1
Figure 1
Multimodal mechanism of action of vortioxetine.

References

    1. World Health Organization (webpage WHO). Depression, let’s talk. World Health Day 2017 campaign. Available from:
    1. Battaglia A, Dubini A, Mannheimer R, Pancheri P. Depression in the Italian community: epidemiology and socio-economic implications. Int Clin Psychopharmacol. 2004;19:135–142.
    1. de Girolamo G, Polidori G, Morosini P, et al. Prevalence of common mental disorders in Italy, risk factors, health status, and utilization of health services: the ESEMeD-WMH project. Epidemiol Psichiatr Soc. 2005;14:1–100.
    1. Castro-Costa E, Dewey M, Stewart R, et al. Prevalence of depressive symptoms and syndromes in later life in ten European countries: the SHARE study. Br J Psychiatry. 2007;191:393–401. doi:10.1192/bjp.bp.107.036772
    1. Copeland JR, Beekman AT, Dewey ME, et al. Depression in Europe. Geographical distribution among older people. Br J Psychiatry. 1999;174:312–321.
    1. Rovner BW, German PS, Brant LJ, Clark R, Burton L, Folstein MF. Depression and mortality in nursing homes. JAMA. 1991;265(8):993–996.
    1. Conradi HJ, Ormel J, de Jonge P. Presence of individual (residual) symptoms during depressive episodes and periods of remission: a 3-year prospective study. Psychol Med. 2011;41(6):1165–1174. doi:10.1017/S0033291710001911
    1. Sonnenberg CM, Deeg DJ, Comijs HC, van Tilburg W, Beekman ATF. Trends in antidepressant use in the older population: results from the LASA-study over a period of 10 years. J Affect Disord. 2008;111(2–3):299–305. doi:10.1016/j.jad.2008.03.009
    1. McIntyre RS, Xiao HX, Syeda K, et al. The prevalence, measurement, and treatment of the cognitive dimension/domain in major depressive disorder. CNS Drugs. 2015;29(7):577–589. doi:10.1007/s40263-015-0263-x
    1. Millan MJ, Agid Y, Brüne M, et al. Cognitive dysfunction in psychiatric disorders: characteristics, causes and the quest for improved therapy. Nat Rev Drug Discov. 2012;11(2):141–168. doi:10.1038/nrd3628
    1. Kiloh LG. Pseudo-dementia. Acta Psychiatr Scand. 1961;37:336–351. doi:10.1111/acp.1961.37.issue-4
    1. Kang H, Zhao F, You L, et al. Pseudo-dementia: a neuropsychological review. Ann Indian Acad Neurol. 2014;17(2):147–154. doi:10.4103/0972-2327.132613
    1. Mahendra B. Depression and dementia: the multi-faceted relationship. Psychol Med. 1985;15:227–236. doi:10.1017/S0033291700023503
    1. Bulbena A, Berrios GE. Pseudodementia: facts and figures. Br J Psychiatry. 1986;148:87–94. doi:10.1192/bjp.148.1.87
    1. Alexopoulos GS, Meyers BS, Young RC, et al. The course of geriatric depression with “reversible dementia”: a controlled study. Am J Psychiatry. 1993;150(11):1693–1699. doi:10.1176/ajp.150.11.1693
    1. Ownby RL, Crocco E, Acevedo A, John V, Loewenstein D. Depression and risk for Alzheimer disease: systematic review, meta-analysis, and metaregression analysis. Arch Gen Psychiatry. 2006;63(5):530–538. doi:10.1001/archpsyc.63.5.530
    1. Sáez-Fonseca JA, Lee L, Walker Z. Long-term outcome of depressive pseudodementia in the elderly. J Affect Disord. 2007;101:123–129. doi:10.1016/j.jad.2006.11.004
    1. Lovestone S. Alzheimer’ s disease and other dementias (including pseudodementias) In: David AS, Fleminger S, Kopelman MD, Lovestone S, Mellers JDC, editors. Lishman’s Organic Psychiatry: A Textbook of Neuropsychiatry. 4th ed. Chichester: Wiley-Blackwell; 2009:566.
    1. Heser K, Bleckwenn M, Wiese B, et al. Late-life depressive symptoms and lifetime history of major depression: cognitive deficits are largely due to incipient dementia rather than depression. J Alzheimers Dis. 2016;54(1):185–199. doi:10.3233/JAD-160209
    1. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 5th ed. Arlington: American Psychiatric Publishing; 2013.
    1. Rabins PV, Lyketsos CG. A commentary on the proposed DSM revision regarding the classification of cognitive disorders. Am J Geriatr Psychiatry. 2011;19:201–204. doi:10.1097/JGP.0b013e3182051ac7
    1. McAllister TW, Price TR. Severe depressive pseudodementia with and without dementia. Am J Psychiatry. 1982;139:626–629. doi:10.1176/ajp.139.5.626
    1. Miskowiak KW, Ott CV, Petersen JZ, Kessing LV. Systematic review of randomized controlled trials of candidate treatments for cognitive impairment in depression and methodological challenges in the field. Eur Neuropsychopharmacol. 2016;26(12):1845–1867. doi:10.1016/j.euroneuro.2016.09.641
    1. Sahin S, Okluoglu Önal T, Cinar N, Bozdemir M, Çubuk R, Karsidag S. Distinguishing depressive pseudodementia from Alzheimer disease: a comparative study of hippocampal volumetry and cognitive tests. Dement Geriatr Cogn Dis Extra. 2017;7(2):230–239. doi:10.1159/000477759
    1. McIntyre RS, Cha DS, Soczynska JK, et al. Cognitive deficits and functional outcomes in major depressive disorder: determinants, substrates, and treatment interventions. Depress Anxiety. 2013;30:515–527. doi:10.1002/da.22063
    1. McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM. Clinical diagnosis of Alzheimer’s disease: report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer’s Disease. Neurology. 1984;34(7):939–944.
    1. Varma AR, Snowden JS, Lloyd JJ, Talbot PR, Mann DM, Neary D. Evaluation of the NINCDS-ADRDA criteria in the differentiation of Alzheimer’s disease and frontotemporal dementia. J Neurol Neurosurg Psychiatry. 1999;66(2):184–188.
    1. Dubois B, Feldman HH, Jacova C, et al. Research criteria for the diagnosis of Alzheimer’s disease: revising the NINCDS-ADRDA criteria. Lancet Neurol. 2007;6(8):734–746. doi:10.1016/S1474-4422(07)70178-3
    1. Dubois B, Feldman HH, Jacova C, et al. Advancing research diagnostic criteria for Alzheimer’s disease: the IWG-2 criteria. Lancet Neurol. 2014;13(6):614–629. doi:10.1016/S1474-4422(14)70090-0
    1. Zhang K, Zhu Y, Zhu Y, et al. Molecular, functional, and structural imaging of major depressive disorder. Neurosci Bull. 2016;32(3):273–285. doi:10.1007/s12264-016-0030-0
    1. Huang M, Lu S, Yu L, et al. Altered fractional amplitude of low frequency fluctuation associated with cognitive dysfunction in first-episode drug-naïve major depressive disorder patients. BMC Psychiatry. 2017;17(1):11. doi:10.1186/s12888-017-1489-6
    1. Kavalali ET, Monteggia LM. Synaptic mechanisms underlying rapid antidepressant action of ketamine. Am J Psychiatry. 2012;169(11):1150–1156. doi:10.1176/appi.ajp.2012.12040531
    1. McIntyre RS. Using measurement strategies to identify and monitor residual symptoms. J Clin Psychiatry. 2013;74(Suppl. 2):14–18. doi:10.4088/JCP.12084su1c.03
    1. Bang-Andersen B, Ruhland T, Jørgensen M, et al. Discovery of 1-[2-(2,4-dimethylphenylsulfanyl)phenyl]piperazine (Lu AA21004): a novel multimodal compound for the treatment of major depressive disorder. J Med Chem. 2011;54(9):3206–3221. doi:10.1021/jm101459g
    1. Stahl SM. Modes and nodes explain the mechanism of action of vortioxetine, a multimodal agent (MMA): enhancing serotonin release by combining serotonin (5HT) transporter inhibition with actions at 5HT receptors (5HT1A, 5HT1B, 5HT1D, 5HT7 receptors). CNS Spectr. 2015;20(2):93–97. doi:10.1017/S1092852915000139
    1. Assié M-B, Lomenech H, Ravailhe V, Faucillon V, Newman-Tancredi A. Rapid desensitization of somatodendritic 5-HT1A receptors by chronic administration of the high-efficacy 5-HT1A agonist, F13714: a microdialysis study in the rat. Br J Pharmacol. 2006;149(2):170–178. doi:10.1038/sj.bjp.0706859
    1. Roychoudhury M, Kulkarni SK. Effects of ondansetron on short-term memory retrieval in mice. Methods Find Exp Clin Pharmacol. 1997;19(1):43–46.
    1. Areberg J, Søgaard B, Højer A-M. The clinical pharmacokinetics of Lu AA21004 and its major metabolite in healthy young volunteers. Basic Clin Pharmacol Toxicol. 2012;111(3):198–205. doi:10.1111/j.1742-7843.2012.00886.x
    1. Hvenegaard MG, Bang-Andersen B, Pedersen H, Jørgensen M, Püschl A, Dalgaard L. Identification of the cytochrome P450 and other enzymes involved in the in vitro oxidative metabolism of a novel antidepressant, Lu AA21004. Drug Metab Dispos. 2012;40(7):1357–1365. doi:10.1124/dmd.112.044610
    1. Jensen JB, Du Jardin KG, Song D, et al. Vortioxetine, but not escitalopram or duloxetine, reverses memory impairment induced by central 5-HT depletion in rats: evidence for direct 5-HT receptor modulation. Eur Neuropsychopharmacol. 2014;24(1):148–159. doi:10.1016/j.euroneuro.2013.10.011
    1. Wallace A, Pehrson AL, Sánchez C, Morilak DA. Vortioxetine restores reversal learning impaired by 5-HT depletion or chronic intermittent cold stress in rats. Int J Neuropsychopharmacol. 2014;17(10):1695–1706. doi:10.1017/S1461145714000571
    1. Westrich L, Haddjeri N, Dkhissi-Benyahya O, Sánchez C. Involvement of 5-HT₇ receptors in vortioxetine‘s modulation of circadian rhythms and episodic memory in rodents. Neuropharmacology. 2015;89:382–390. doi:10.1016/j.neuropharm.2014.10.015
    1. de Bartolomeis A, Fagiolini A, Maina G. Vortioxetine in the treatment of major depression. Riv Psichiatr. 2016;51(6):215–230. doi:10.1708/2596.26720
    1. Pehrson AL, Cremers T, Bétry C, et al. Lu AA21004, a novel multimodal antidepressant, produces regionally selective increases of multiple neurotransmitters – a rat microdialysis and electrophysiology study. Eur Neuropsychopharmacol. 2013;23(2):133–145. doi:10.1016/j.euroneuro.2012.04.006
    1. 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. doi:10.1016/j.pharmthera.2014.07.001
    1. Bétry C, Pehrson AL, Etiévant A, Ebert B, Sánchez C, Haddjeri N. The rapid recovery of 5-HT cell firing induced by the antidepressant vortioxetine involves 5-HT(3) receptor antagonism. Int J Neuropsychopharmacol. 2013;16(5):1115–1127. doi:10.1017/S1461145712001058
    1. Chen F, du Jardin KG, Waller JA, Sanchez C, Nyengaard JR, Wegener G. Vortioxetine promotes early changes in dendritic morphology compared to fluoxetine in rat hippocampus. Eur Neuropsychopharmacol. 2016;26(2):234–245. doi:10.1016/j.euroneuro.2015.12.018
    1. Waller JA, Chen F, Sánchez C. Vortioxetine promotes maturation of dendritic spines in vitro: a comparative study in hippocampal cultures. Neuropharmacology. 2016;103:143–154. doi:10.1016/j.neuropharm.2015.12.012
    1. Bétry C, Etiévant A, Pehrson A, Sánchez C, Haddjeri N. Effect of the multimodal acting antidepressant vortioxetine on rat hippocampal plasticity and recognition memory. Prog Neuropsychopharmacol Biol Psychiatry. 2015;58:38–46. doi:10.1016/j.pnpbp.2014.12.002
    1. Guilloux J-P, Mendez-David I, Pehrson A, et al. Antidepressant and anxiolytic potential of the multimodal antidepressant vortioxetine (Lu AA21004) assessed by behavioural and neurogenesis outcomes in mice. Neuropharmacology. 2013;73:147–159. doi:10.1016/j.neuropharm.2013.05.014
    1. Felice D, Guilloux J-P, Pehrson A, et al. Vortioxetine improves context discrimination in mice through a neurogenesis independent mechanism. Front Pharmacol. 2018;9:204. doi:10.3389/fphar.2018.00204
    1. Lu Y, Ho CS, McIntyre RS, Wang W, Ho RC. Effects of vortioxetine and fluoxetine on the level of brain derived neurotrophic factors (BDNF) in the hippocampus of chronic unpredictable mild stress-induced depressive rats. Brain Res Bull. 2018;142:1–7. doi:10.1016/j.brainresbull.2018.06.007
    1. Koesters M, Ostuzzi G, Guaiana G, et al. Vortioxetine for depression in adults. Cochrane Database Syst Rev. 2017;7:CD011520. doi:10.1002/14651858.CD003881.pub4
    1. Frampton JE. Vortioxetine: a review in cognitive dysfunction in depression. Drugs. 2016;76(17):1675–1682. doi:10.1007/s40265-016-0655-3
    1. McIntyre RS, Lophaven S, Olsen CK. A randomized, double-blind, placebo-controlled study of vortioxetine on cognitive function in depressed adults. Int J Neuropsychopharmacol. 2014;17(10):1557–1567. doi:10.1017/S1461145714000546
    1. Mahableshwarkar AR, Zajecka J, Jacobson W, Chen Y, Keefe RS. A randomized, placebo-controlled, active-reference, double-blind, flexible-dose study of the efficacy of vortioxetine on cognitive function in major depressive disorder. Neuropsychopharmacology. 2016;41(12):2961. doi:10.1038/npp.2016.181
    1. 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(4):215–223. doi:10.1097/YIC.0b013e3283542457
    1. Freeman MP, Cheng LJ, Moustafa D, et al. Vortioxetine for major depressive disorder, vasomotor, and cognitive symptoms associated with the menopausal transition. Ann Clin Psychiatry. 2017;29(4):249–257.
    1. Mahableshwarkar AR, Zajecka J, Jacobson W, Chen Y, Keefe RS. 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(8):2025–2037. doi:10.1038/npp.2015.52
    1. Areberg J, Luntang-Jensen M, Søgaard B, Nilausen DØ. Occupancy of the serotonin transporter after administration of Lu AA21004 and its relation to plasma concentration in healthy subjects. Basic Clin Pharmacol Toxicol. 2012;110(4):401–404. doi:10.1111/j.1742-7843.2011.00810.x
    1. Stenkrona P, Halldin C, Lundberg J. 5-HTT and 5-HT(1A) receptor occupancy of the novel substance vortioxetine (Lu AA21004). A PET study in control subjects. Eur Neuropsychopharmacol. 2013;23(10):1190–1198. doi:10.1016/j.euroneuro.2013.01.002
    1. Alvarez E, Perez V, Artigas F. Pharmacology and clinical potential of vortioxetine in the treatment of major depressive disorder. Neuropsychiatr Dis Treat. 2014;10:1297–1307. doi:10.2147/NDT.S41387
    1. Baldwin DS, Chrones L, Florea I, et al. The safety and tolerability of vortioxetine: analysis of data from randomized placebo-controlled trials and open-label extension studies. J Psychopharmacol. 2016;30(3):242–252. doi:10.1177/0269881116628440
    1. Pearce EF, Murphy JA. Vortioxetine for the treatment of depression. Ann Pharmacother. 2014;48(6):758–765. doi:10.1177/1060028014528305
    1. Citrome L. Vortioxetine for major depressive disorder: an indirect comparison with duloxetine, escitalopram, levomilnacipran, sertraline, venlafaxine, and vilazodone, using number needed to treat, number needed to harm, and likelihood to be helped or harmed. J Affect Disord. 2016;196:225–233. doi:10.1016/j.jad.2016.02.042
    1. Saragoussi D, Christensen MC, Hammer-Helmich L, Rive B, Touya M, Haro JM. Long-term follow-up on health-related quality of life in major depressive disorder: a 2-year European cohort study. Neuropsychiatr Dis Treat. 2018;14:1339–1350. doi:10.2147/NDT.S159276
    1. Rosenblat JD, Kakar R, McIntyre RS. The cognitive effects of antidepressants in major depressive disorder: a systematic review and meta-analysis of randomized clinical trials. Int J Neuropsychopharmacol. 2015;19(2). pii:pyv082. doi:10.1093/ijnp/pyv082.
    1. McIntyre RS, Lee Y. Cognition in major depressive disorder: a ‘Systemically Important Functional Index‘ (SIFI). Curr Opin Psychiatry. 2016;29(1):48–55. doi:10.1097/YCO.0000000000000221
    1. Albert U, Brugnoli R, Caraci F, et al. Italian psychiatrists‘ perception on cognitive symptoms in major depressive disorder. Int J Psychiatry Clin Pract. 2016;20(1):2–9. doi:10.3109/13651501.2015.1093147

Source: PubMed

3
Subscribe