Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Transcriptomic signatures of treatment response to the combination of escitalopram and memantine or placebo in late-life depression

Molecular Psychiatry volume 26, pages 5171–5179 (2021)Cite this article

Subjects

Abstract

Drugs that target glutamate neuronal transmission, such as memantine, offer a novel approach to the treatment of late-life depression, which is frequently comorbid with cognitive impairment. The results of our recently published double-blind, randomized, placebo-controlled trial of escitalopram or escitalopram/memantine in late-life depression with subjective memory complaints (NCT01902004) indicated no differences between treatments in depression remission, but additional benefits in cognition at 12-month follow-up with combination treatment. To identify pathways and biological functions uniquely induced by combination treatment that may explain cognitive improvements, we generated transcriptional profiles of remission compared with non-remission from whole blood samples. Remitters to escitalopram compared with escitalopram/memantine combination treatment display unique patterns of gene expression at baseline and 6 months after treatment initiation. Functional enrichment analysis demonstrates that escitalopram-based remission associates to functions related to cellular proliferation, apoptosis, and inflammatory response. Escitalopram/memantine-based remission, however, is characterized by processes related to cellular clearance, metabolism, and cytoskeletal dynamics. Both treatments modulate inflammatory responses, albeit via different effector pathways. Additional research is needed to understand the implications of these results in explaining the observed superior effects of combination treatment on cognition observed with prolonged treatment.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: ESC/PBO and ESC/MEM remission profiles differ pre- and post-treatment.
Fig. 2: Signaling pathways uniquely enriched by ESC/PBO and ESC/MEM remitters compared with non-remitters.
Fig. 3: Leading edge analysis of ESC/PBO and ESC/MEM enriched gene sets.
Fig. 4: Network analysis of enriched gene sets in ESC/PBO and ESC/MEM remitters compared with non-remitters.

Similar content being viewed by others

References

  1. Conwell Y, Duberstein PR, Cox C, Herrmann J, Forbes N, Caine ED. Age differences in behaviors leading to completed suicide. Am J Geriatr Psychiatry. 1998;6:122–6.

    CAS  PubMed  Google Scholar 

  2. Lavretsky H, Lesser IM, Wohl M, Miller BL. Relationship of age, age at onset, and sex to depression in older adults. Am J Geriatr Psychiatry. 1998;6:248–56.

    CAS  PubMed  Google Scholar 

  3. Rush AJ, Trivedi MH, Wisniewski SR, Nierenberg AA, Stewart JW, Warden D, et al. Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report. Am J Psychiatry. 2006;163:1905–17.

    PubMed  Google Scholar 

  4. Reynolds CF 3rd, Dew MA, Pollock BG, Mulsant BH, Frank E, Miller MD, et al. Maintenance treatment of major depression in old age. N Engl J Med. 2006;354:1130–8.

    CAS  PubMed  Google Scholar 

  5. Bhalla RK, Butters MA, Becker JT, Houck PR, Snitz BE, Lopez OL, et al. Patterns of mild cognitive impairment after treatment of depression in the elderly. Am J Geriatr Psychiatry. 2009;17:308–16.

    PubMed  PubMed Central  Google Scholar 

  6. Steffens DC. Separating mood disturbance from mild cognitive impairment in geriatric depression. Int Rev Psychiatry. 2008;20:374–81.

    PubMed  Google Scholar 

  7. Vega JN, Zurkovsky L, Albert K, Melo A, Boyd B, Dumas J, et al. Altered brain connectivity in early postmenopausal women with subjective cognitive impairment. Front Neurosci. 2016;10:433.

    PubMed  PubMed Central  Google Scholar 

  8. Bauer ME, Teixeira AL. Inflammation in psychiatric disorders: what comes first? Ann NY Acad Sci. 2019;1437:57–67.

    CAS  PubMed  Google Scholar 

  9. Lavretsky H, Laird KT, Krause-Sorio B, Heimberg BF, Yeargin J, Grzenda A, et al. A randomized double-blind placebo-controlled trial of combined escitalopram and memantine for older adults with major depression and subjective memory complaints. Am J Geriatr Psychiatry. 2020;28:178–90.

    PubMed  Google Scholar 

  10. Pelton GH, Harper OL, Roose SP, Marder K, D’Antonio K, Devanand DP. Combined treatment with memantine/es‐citalopram for older depressed patients with cognitive impairment: a pilot study. Int J Geriatr Psychiatry. 2016;31:648–55.

    PubMed  Google Scholar 

  11. Zhu GQ, Li JY, He L, Wang XC, Hong XQ. MPTP-induced changes in hippocampal synaptic plasticity and memory are prevented by memantine through the BDNF-TrkB pathway. Br J Pharm. 2015;172:2354–68.

    CAS  Google Scholar 

  12. Maekawa M, Namba T, Suzuki E, Yuasa S, Kohsaka S, Uchino S. NMDA receptor antagonist memantine promotes cell proliferation and production of mature granule neurons in the adult hippocampus. Neurosci Res. 2009;63:259–66.

    CAS  PubMed  Google Scholar 

  13. Ficek J, Zygmunt M, Piechota M, Hoinkis D, Rodriguez Parkitna J, Przewlocki R, et al. Molecular profile of dissociative drug ketamine in relation to its rapid antidepressant action. BMC Genom. 2016;17:362.

    Google Scholar 

  14. Drever BD, Anderson WG, Johnson H, O’Callaghan M, Seo S, Choi DY, et al. Memantine acts as a cholinergic stimulant in the mouse hippocampus. J Alzheimers Dis. 2007;12:319–33.

    CAS  PubMed  Google Scholar 

  15. Nyakas C, Granic I, Halmy LG, Banerjee P, Luiten PG. The basal forebrain cholinergic system in aging and dementia. Rescuing cholinergic neurons from neurotoxic amyloid-beta42 with memantine. Behav Brain Res. 2011;221:594–603.

    CAS  PubMed  Google Scholar 

  16. Wang YC, Sanchez-Mendoza EH, Doeppner TR, Hermann DM. Post-acute delivery of memantine promotes post-ischemic neurological recovery, peri-infarct tissue remodeling, and contralesional brain plasticity. J Cereb Blood Flow Metab. 2017;37:980–93.

    PubMed  Google Scholar 

  17. Lopez-Valdes HE, Clarkson AN, Ao Y, Charles AC, Carmichael ST, Sofroniew MV, et al. Memantine enhances recovery from stroke. Stroke. 2014;45:2093–100.

    PubMed  PubMed Central  Google Scholar 

  18. Wong P, Leppert IR, Roberge D, Boudam K, Brown PD, Muanza T, et al. A pilot study using dynamic contrast enhanced-MRI as a response biomarker of the radioprotective effect of memantine in patients receiving whole brain radiotherapy. Oncotarget. 2016;7:50986–96.

    PubMed  PubMed Central  Google Scholar 

  19. Duman JG, Dinh J, Zhou W, Cham H, Mavratsas VC, Paveskovic M, et al. Memantine prevents acute radiation-induced toxicities at hippocampal excitatory synapses. Neuro Oncol. 2018;20:655–65.

    CAS  PubMed  Google Scholar 

  20. Lynch M. Preservation of cognitive function following whole brain radiotherapy in patients with brain metastases: complications, treatments, and the emerging role of memantine. J Oncol Pharm Pract. 2019;25:657–62.

    CAS  PubMed  Google Scholar 

  21. Yoon WS, Yeom MY, Kang ES, Chung YA, Chung DS, Jeun SS. Memantine induces NMDAR1-mediated autophagic cell death in malignant glioma cells. J Korean Neurosurg Soc. 2017;60:130–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Cacciatore I, Fornasari E, Marinelli L, Eusepi P, Ciulla M, Ozdemir O, et al. Memantine-derived drugs as potential antitumor agents for the treatment of glioblastoma. Eur J Pharm Sci. 2017;109:402–11.

    CAS  PubMed  Google Scholar 

  23. Wang F, Zou Z, Gong Y, Yuan D, Chen X, Sun T. Regulation of human brain microvascular endothelial cell adhesion and barrier functions by memantine. J Mol Neurosci. 2017;62:123–9.

    CAS  PubMed  Google Scholar 

  24. Wu HM, Tzeng NS, Qian L, Wei SJ, Hu X, Chen SH, et al. Novel neuroprotective mechanisms of memantine: increase in neurotrophic factor release from astroglia and anti-inflammation by preventing microglial activation. Neuropsychopharmacology. 2009;34:2344–57.

    CAS  PubMed  Google Scholar 

  25. Huber W, Carey VJ, Gentleman R, Anders S, Carlson M, Carvalho BS, et al. Orchestrating high-throughput genomic analysis with bioconductor. Nat Methods. 2015;12:115–21.

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Carvalho BS, Irizarry RA. A framework for oligonucleotide microarray preprocessing. Bioinformatics. 2010;26:2363–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Ritchie ME, Phipson B, Wu D, Hu Y, Law CW, Shi W, et al. limma powers differential expression analyses for RNA-sequencing and microarray studies. Nucleic Acids Res. 2015;43:e47.

    PubMed  PubMed Central  Google Scholar 

  28. Benjamini Y, Drai D, Elmer G, Kafkafi N, Golani I. Controlling the false discovery rate in behavior genetics research. Behav Brain Res. 2001;125:279–84.

    CAS  PubMed  Google Scholar 

  29. Plaisier SB, Taschereau R, Wong JA, Graeber TG. Rank-rank hypergeometric overlap: identification of statistically significant overlap between gene-expression signatures. Nucleic Acids Res. 2010;38:e169.

    PubMed  PubMed Central  Google Scholar 

  30. Sergushichev A. An algorithm for fast preranked gene set enrichment analysis using cumulative statistic calculation. BioRxiv. 2016. https://doi.org/10.1101/060012.

  31. Isserlin R, Merico D, Voisin V, Bader GD. Enrichment map—a Cytoscape app to visualize and explore OMICs pathway enrichment results. F1000 Res. 2014;3:141.

    Google Scholar 

  32. Shannon P, Markiel A, Ozier O, Baliga NS, Wang JT, Ramage D, et al. Cytoscape: a software environment for integrated models of biomolecular interaction networks. Genome Res. 2003;13:2498–504.

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Castren E, Hen R. Neuronal plasticity and antidepressant actions. Trends Neurosci. 2013;36:259–67.

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Taupin P. Neurogenesis and the effect of antidepressants. Drug Target Insights. 2006;1:13–17.

    PubMed  PubMed Central  Google Scholar 

  35. Liu Y, Huang Y, Xu Y, Qu P, Wang M. Memantine protects against ischemia/reperfusion-induced brain endothelial permeability. IUBMB Life. 2018;70:336–43.

    CAS  PubMed  Google Scholar 

  36. Paltsev MA, Zuev VA, Kozhevnikova EO, Linkova NS, Kvetnaia TV, Polyakova VO, et al. Molecular markers of early diagnosis of Alzheimer disease: prospects for research in peripheral tissues. Adv Gerontol. 2018;8:111–8.

    Google Scholar 

  37. Anacker C, Zunszain PA, Cattaneo A, Carvalho LA, Garabedian MJ, Thuret S, et al. Antidepressants increase human hippocampal neurogenesis by activating the glucocorticoid receptor. Mol Psychiatry. 2011;16:738–50.

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Malykhin NV, Carter R, Seres P, Coupland NJ. Structural changes in the hippocampus in major depressive disorder: contributions of disease and treatment. J Psychiatry Neurosci. 2010;35:337–43.

    PubMed  PubMed Central  Google Scholar 

  39. Bocchio-Chiavetto L, Maffioletti E, Bettinsoli P, Giovannini C, Bignotti S, Tardito D, et al. Blood microRNA changes in depressed patients during antidepressant treatment. Eur Neuropsychopharmacol. 2013;23:602–11.

    CAS  PubMed  Google Scholar 

  40. Pettai K, Milani L, Tammiste A, Vosa U, Kolde R, Eller T, et al. Whole-genome expression analysis reveals genes associated with treatment response to escitalopram in major depression. Eur Neuropsychopharmacol. 2016;26:1475–83.

    CAS  PubMed  Google Scholar 

  41. Konietzny A, Bar J, Mikhaylova M. Dendritic actin cytoskeleton: structure, functions, and regulations. Front Cell Neurosci. 2017;11:147.

    PubMed  PubMed Central  Google Scholar 

  42. Levkovitz Y, Gil-Ad I, Zeldich E, Dayag M, Weizman A. Differential induction of apoptosis by antidepressants in glioma and neuroblastoma cell lines. J Mol Neurosci. 2005;27:29–42.

    CAS  PubMed  Google Scholar 

  43. Rizzoli R, Cooper C, Reginster JY, Abrahamsen B, Adachi JD, Brandi ML, et al. Antidepressant medications and osteoporosis. Bone. 2012;51:606–13.

    CAS  PubMed  Google Scholar 

  44. Galecki P, Mossakowska-Wojcik J, Talarowska M. The anti-inflammatory mechanism of antidepressants—SSRIs, SNRIs. Prog Neuropsychopharmacol Biol Psychiatry. 2018;80(Pt C):291–4.

    CAS  PubMed  Google Scholar 

  45. Ellul P, Mariotti-Ferrandiz E, Leboyer M, Klatzmann D. Regulatory T cells as supporters of psychoimmune resilience: toward immunotherapy of major depressive disorder. Front Neurol. 2018;9:167.

    PubMed  PubMed Central  Google Scholar 

  46. Szalach LP, Lisowska KA, Cubala WJ. The influence of antidepressants on the immune system. Arch Immunol Ther Exp. 2019;67:143–51.

    CAS  Google Scholar 

  47. Babic Leko M, Willumsen N, Nikolac Perkovic M, Klepac N, Borovecki F, Hof PR, et al. Association of MAPT haplotype-tagging polymorphisms with cerebrospinal fluid biomarkers of Alzheimer’s disease: a preliminary study in a Croatian cohort. Brain Behav. 2018;8:e01128.

    PubMed  PubMed Central  Google Scholar 

  48. Lasky JL, Wu H. Notch signaling, brain development, and human disease. Pediatr Res. 2005;57:104–9.

    Google Scholar 

  49. Yao PJ, Petralia RS, Mattson MP. Sonic Hedgehog signaling and hippocampal neuroplasticity. Trends Neurosci. 2016;39:840–50.

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Shih RH, Wang CY, Yang CM. NF-kappa B signaling pathways in neurological inflammation: a mini review. Front Mol Neurosci. 2015;8:77.

    PubMed  PubMed Central  Google Scholar 

  51. Jantas D, Szymanska M, Budziszewska B, Lason W. An involvement of BDNF and PI3-K/Akt in the anti-apoptotic effect of memantine on staurosporine-evoked cell death in primary cortical neurons. Apoptosis. 2009;14:900–12.

    CAS  PubMed  Google Scholar 

  52. Volbracht C, van Beek J, Zhu C, Blomgren K, Leist M. Neuroprotective properties of memantine in different in vitro and in vivo models of excitotoxicity. Eur J Neurosci. 2006;23:2611–22.

    PubMed  Google Scholar 

  53. Albayrak G, Konac E, Dikmen AU, Bilen CY. Memantine induces apoptosis and inhibits cell cycle progression in LNCaP prostate cancer cells. Hum Exp Toxicol. 2018;37:953–8.

    CAS  PubMed  Google Scholar 

  54. Folch J, Ettcheto M, Busquets O, Sánchez-López E, Castro-Torres RD, Verdaguer E, et al. The implication of the brain insulin receptor in late onset Alzheimer’s disease dementia. Pharmaceuticals. 2018;11:11.

    PubMed Central  Google Scholar 

  55. Huang X-T, Li C, Peng X-P, Guo J, Yue S-J, Liu W, et al. An excessive increase in glutamate contributes to glucose-toxicity in β-cells via activation of pancreatic NMDA receptors in rodent diabetes. Sci Rep. 2017;7:44120.

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Ettcheto M, Sánchez-López E, Gómez-Mínguez Y, Cabrera H, Busquets O, Beas-Zarate C, et al. Peripheral and central effects of memantine in a mixed preclinical mice model of obesity and familial Alzheimer’s disease. Mol Neurobiol. 2018;55:7327–39.

    CAS  PubMed  Google Scholar 

  57. Ota H, Ogawa S, Ouchi Y, Akishita M. Protective effects of NMDA receptor antagonist, memantine, against senescence of PC12 cells: a possible role of nNOS and combined effects with donepezil. Exp Gerontol. 2015;72:109–16.

    CAS  PubMed  Google Scholar 

  58. Dong J, Zhou M, Wu X, Du M, Wang X. Memantine combined with environmental enrichment improves spatial memory and alleviates Alzheimer’s disease-like pathology in senescence-accelerated prone-8 (SAMP8) mice. J Biomed Res. 2012;26:439–47.

    CAS  PubMed  PubMed Central  Google Scholar 

  59. Campisi J. Aging, cellular senescence, and cancer. Annu Rev Physiol. 2013;75:685–705.

    CAS  PubMed  Google Scholar 

  60. Diniz BS, Reynolds CF 3rd, Sibille E, Lin C-W, Tseng G, Lotrich F, et al. Enhanced molecular aging in late-life depression: the senescent-associated secretory phenotype. Am J Geriatr Psychiatry. 2017;25:64–72.

    PubMed  Google Scholar 

  61. Diniz BS, Reynolds Iii CF, Sibille E, Bot M, Penninx BWJH. Major depression and enhanced molecular senescence abnormalities in young and middle-aged adults. Transl Psychiatry. 2019;9:198.

    PubMed  PubMed Central  Google Scholar 

  62. Zhu Y, Tchkonia T, Pirtskhalava T, Gower AC, Ding H, Giorgadze N, et al. The Achilles’ heel of senescent cells: from transcriptome to senolytic drugs. Aging Cell. 2015;14:644–58.

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Childs BG, Baker DJ, Kirkland JL, Campisi J, van Deursen JM. Senescence and apoptosis: dueling or complementary cell fates? EMBO Rep. 2014;15:1139–53.

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Menendez JA, Alarcon T. Senescence-inflammatory regulation of reparative cellular reprogramming in aging and cancer. Front Cell Dev Biol. 2017;5:49.

    PubMed  PubMed Central  Google Scholar 

  65. Imayoshi I, Kageyama R. The role of Notch signaling in adult neurogenesis. Mol Neurobiol. 2011;44:7–12.

    CAS  PubMed  Google Scholar 

  66. Yousef H, Morgenthaler A, Schlesinger C, Bugaj L, Conboy IM, Schaffer DV. Age-associated Increase in BMP signaling inhibits hippocampal neurogenesis. Stem Cells. 2015;33:1577–88.

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Sullivan PF, Fan C, Perou CM. Evaluating the comparability of gene expression in blood and brain. Am J Med Genet B Neuropsychiatr Genet. 2006;141B:261–8.

    PubMed  Google Scholar 

Download references

Acknowledgements

This work was funded by the NIH grants R01MH097892; AT009198 to HL. This work was further supported by NIH grants MH097892, AT009198, and the National Center for Advancing Translational Science (NCATS) UCLA CTSI Grant Number UL1TR001881. AG was partly funded by a research fellowship from the American Psychiatric Association Foundation. The authors thank the Semel Institute Biostatistics Core (SIStat) for database management and support.

Author information

Authors and Affiliations

  1. Jane and Terry Semel Institute for Neuroscience and Human Behavior, Department of Pscyhiatry and Biobehavioral Sciences, David Geffen School of Medicine, University of California, Los Angeles, CA, USA

    Adrienne Grzenda, Prabha Siddarth, Kelsey T. Laird, Jillian Yeargin & Helen Lavretsky

Authors
  1. Adrienne Grzenda
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Prabha Siddarth
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Kelsey T. Laird
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jillian Yeargin
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Helen Lavretsky
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Helen Lavretsky.

Ethics declarations

Conflict of interest

HL received research support from Allergan/Forest Laboratories. All other authors report no financial relationships with commercial interests.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Grzenda, A., Siddarth, P., Laird, K.T. et al. Transcriptomic signatures of treatment response to the combination of escitalopram and memantine or placebo in late-life depression. Mol Psychiatry 26, 5171–5179 (2021). https://doi.org/10.1038/s41380-020-0752-2

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41380-020-0752-2

Search

Advanced search

Quick links