Cognitive Outcomes with Sequential Escitalopram Monotherapy and Adjunctive Aripiprazole Treatment in Major Depressive Disorder: A Canadian Biomarker Integration Network in Depression (CAN-BIND-1) Report

Abstract

Background

Cognitive deficits are detectable in major depressive disorder (MDD). The cognitive impact of antidepressants remains unclear, as does the cognitive effects of aripiprazole in MDD, a commonly used adjunct with putative pro-cognitive properties.

Objectives

In this multi-centre, open-label study, cognitive changes associated with escitalopram monotherapy and adjunctive aripiprazole were examined.

Methods

Acutely depressed participants with MDD (n = 209) received 8 weeks of escitalopram. Non-responders received an additional 8 weeks of adjunctive aripiprazole (ESC-ARI, n = 88), while responders (ESC-CONT, n = 82) continued escitalopram monotherapy (n = 39 lost to attrition). ESC-ARI, ESC-CONT and matched healthy participants (n = 112) completed the Central Nervous System Vital Signs cognitive battery at baseline, 8 and 16 weeks. Linear mixed models compared participants with MDD cognitive trajectories with healthy participants.

Results

Participants with MDD displayed poorer baseline global cognition (assessed via the Neurocognitive Index), composite memory and psychomotor speed vs healthy participants. There were no statistically significant changes in participants with MDD receiving escitalopram monotherapy from baseline to week 8 in the neurocognitive index, reaction time, complex attention, cognitive flexibility, memory or psychomotor speed. Overall symptom severity changes were not associated with cognitive changes. The ESC-CONT group displayed no significant cognitive changes from weeks 8 to 16; reaction time worsened in the ESC-ARI group (p = 0.008) from weeks 8 to 16, independent of symptom change.

Conclusions

Escitalopram monotherapy in acute MDD did not result in significant cognitive improvements. We provide novel evidence that escitalopram continuation in responders does not adversely affect cognition, but adjunctive aripiprazole in escitalopram non-responders worsens reaction time. Treatments targeting cognitive dysfunction are needed in MDD.

ClinicalTrials.gov identifier

NCT01655706; 2 August, 2012.

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

Fig. 1

References

  1. 1.

    Rock PL, Roiser JP, Riedel WJ, Blackwell AD. Cognitive impairment in depression: a systematic review and meta-analysis. Psychol Med. 2014;44(10):2029–40.

    CAS  PubMed  Google Scholar 

  2. 2.

    Bora E, Harrison BJ, Yucel M, Pantelis C. Cognitive impairment in euthymic major depressive disorder: a meta-analysis. Psychol Med. 2013;43(10):2017–26.

    CAS  PubMed  Google Scholar 

  3. 3.

    Evans VC, Iverson GL, Yatham LN, Lam RW. The relationship between neurocognitive and psychosocial functioning in major depressive disorder: a systematic review. J Clin Psychiatry. 2014;75(12):1359–70.

    PubMed  Google Scholar 

  4. 4.

    Bortolato B, Miskowiak KW, Kohler CA, Maes M, Fernandes BS, Berk M, et al. Cognitive remission: a novel objective for the treatment of major depression? BMC Med. 2016;14:9.

    PubMed  PubMed Central  Google Scholar 

  5. 5.

    Semkovska M, Quinlivan L, O’Grady T, Johnson R, Collins A, O’Connor J, et al. Cognitive function following a major depressive episode: a systematic review and meta-analysis. Lancet Psychiatry. 2019;6(10):851–61.

    PubMed  Google Scholar 

  6. 6.

    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):pyv082.

    PubMed  PubMed Central  Google Scholar 

  7. 7.

    Prado CE, Watt S, Crowe SF. A meta-analysis of the effects of antidepressants on cognitive functioning in depressed and non-depressed samples. Neuropsychol Rev. 2018;28(1):32–72.

    PubMed  Google Scholar 

  8. 8.

    Baune BT, Renger L. Pharmacological and non-pharmacological interventions to improve cognitive dysfunction and functional ability in clinical depression: a systematic review. Psychiatry Res. 2014;219(1):25–50.

    PubMed  Google Scholar 

  9. 9.

    Keefe RS, McClintock SM, Roth RM, Doraiswamy PM, Tiger S, Madhoo M. Cognitive effects of pharmacotherapy for major depressive disorder: a systematic review. J Clin Psychiatry. 2014;75(8):864–76.

    PubMed  Google Scholar 

  10. 10.

    Shilyansky C, Williams LM, Gyurak A, Harris A, Usherwood T, Etkin A. Effect of antidepressant treatment on cognitive impairments associated with depression: a randomised longitudinal study. Lancet Psychiatry. 2016;3(5):425–35.

    PubMed  PubMed Central  Google Scholar 

  11. 11.

    Andrade C, Rao NS. How antidepressant drugs act: a primer on neuroplasticity as the eventual mediator of antidepressant efficacy. Indian J Psychiatry. 2010;52(4):378–86.

    PubMed  PubMed Central  Google Scholar 

  12. 12.

    Liu B, Liu J, Wang M, Zhang Y, Li L. From serotonin to neuroplasticity: evolvement of theories for major depressive disorder. Front Cell Neurosci. 2017;11:305.

    CAS  PubMed  PubMed Central  Google Scholar 

  13. 13.

    Nagane A, Baba H, Nakano Y, Maeshima H, Hukatsu M, Ozawa K, et al. Comparative study of cognitive impairment between medicated and medication-free patients with remitted major depression: class-specific influence by tricyclic antidepressants and newer antidepressants. Psychiatry Res. 2014;218(1–2):101–5.

    PubMed  Google Scholar 

  14. 14.

    Kennedy SH, Lam RW, McIntyre RS, Tourjman SV, Bhat V, Blier P, et al. Canadian Network for Mood and Anxiety Treatments (CANMAT) 2016 clinical guidelines for the management of adults with major depressive disorder: Section 3. Pharmacological treatments. Can J Psychiatry. 2016;61(9):540–60.

    PubMed  PubMed Central  Google Scholar 

  15. 15.

    Burda K, Czubak A, Kus K, Nowakowska E, Ratajczak P, Zin J. Influence of aripiprazole on the antidepressant, anxiolytic and cognitive functions of rats. Pharmacol Rep. 2011;63(4):898–907.

    CAS  PubMed  Google Scholar 

  16. 16.

    Topolov MK, Getova DP. Cognitive impairment in schizophrenia, neurotransmitters and the new atypical antipsychotic aripiprazole. Folia Med (Plovdiv). 2016;58(1):12–8.

    PubMed  Google Scholar 

  17. 17.

    Russo E, Citraro R, Davoli A, Gallelli L, Di Paola ED, De Sarro G. Ameliorating effects of aripiprazole on cognitive functions and depressive-like behavior in a genetic rat model of absence epilepsy and mild-depression comorbidity. Neuropharmacology. 2013;64:371–9.

    CAS  PubMed  Google Scholar 

  18. 18.

    Bervoets C, Morrens M, Vansteelandt K, Kok F, de Patoul A, Halkin V, et al. Effect of aripiprazole on verbal memory and fluency in schizophrenic patients: results from the ESCAPE study. CNS Drugs. 2012;26(11):975–82.

    CAS  PubMed  Google Scholar 

  19. 19.

    Maat A, Cahn W, Gijsman HJ, Hovens JE, Kahn RS, Aleman A. Open, randomized trial of the effects of aripiprazole versus risperidone on social cognition in schizophrenia. Eur Neuropsychopharmacol. 2014;24(4):575–84.

    CAS  PubMed  Google Scholar 

  20. 20.

    Yasui-Furukori N, Kaneda A, Sugawara N, Tomita T, Kaneko S. Effect of adjunctive treatment with aripiprazole to atypical antipsychotics on cognitive function in schizophrenia patients. J Psychopharmacol. 2012;26(6):806–12.

    PubMed  Google Scholar 

  21. 21.

    Greer TLSP, Grannemann BD, Trivedi MH. Cognitive and psychosocial improvements following aripiprazole augmentation of SSRI antidepressant therapy in treatment-refractory depression: a pilot study. Open J Depression. 2013;2(4):45–53.

    Google Scholar 

  22. 22.

    Lam RW, Milev R, Rotzinger S, Andreazza AC, Blier P, Brenner C, et al. Discovering biomarkers for antidepressant response: protocol from the Canadian Biomarker Integration Network in Depression (CAN-BIND) and clinical characteristics of the first patient cohort. BMC Psychiatry. 2016;16:105.

    PubMed  PubMed Central  Google Scholar 

  23. 23.

    Woodward ND, Purdon SE, Meltzer HY, Zald DH. A meta-analysis of cognitive change with haloperidol in clinical trials of atypical antipsychotics: dose effects and comparison to practice effects. Schizophr Res. 2007;89(1–3):211–24.

    PubMed  Google Scholar 

  24. 24.

    Kennedy SH, Lam RW, Rotzinger S, Milev RV, Blier P, Downar J, et al. Symptomatic and functional outcomes and early prediction of response to escitalopram monotherapy and sequential adjunctive aripiprazole therapy in patients with major depressive disorder: a CAN-BIND-1 report. J Clin Psychiatry. 2019;80(2):18m12202.

    PubMed  Google Scholar 

  25. 25.

    Chakrabarty T, Harkness KL, McInerney SJ, Quilty LC, Milev RV, Kennedy SH, et al. Childhood maltreatment and cognitive functioning in patients with major depressive disorder: a CAN-BIND-1 report. Psychol Med. 2020;50(15):2536–47.

    PubMed  Google Scholar 

  26. 26.

    Sheehan DV, Lecrubier Y, Sheehan KH, Amorim P, Janavs J, Weiller E, et al. The Mini-International Neuropsychiatric Interview (M.I.N.I.): the development and validation of a structured diagnostic psychiatric interview for DSM-IV and ICD-10. J Clin Psychiatry. 1998;59(Suppl. 20):22–33 (quiz 4–57).

    PubMed  Google Scholar 

  27. 27.

    Montgomery SA, Asberg M. A new depression scale designed to be sensitive to change. Br J Psychiatry. 1979;134:382–9.

    CAS  PubMed  Google Scholar 

  28. 28.

    Gualtieri CT, Johnson LG. Reliability and validity of a computerized neurocognitive test battery, CNS vital signs. Arch Clin Neuropsychol. 2006;21(7):623–43.

    PubMed  Google Scholar 

  29. 29.

    Gualtieri CT, Johnson LG. Efficient allocation of attentional resources in patients with ADHD: maturational changes from age 10 to 29. J Atten Disord. 2006;9(3):534–42.

    PubMed  Google Scholar 

  30. 30.

    Gualtieri CT, Johnson LG. Antidepressant side effects in children and adolescents. J Child Adolesc Psychopharmacol. 2006;16(1–2):147–57.

    PubMed  Google Scholar 

  31. 31.

    Gualtieri CT, Johnson LG, Benedict KB. Neurocognition in depression: patients on and off medication versus healthy comparison subjects. J Neuropsychiatry Clin Neurosci. 2006;18(2):217–25.

    PubMed  Google Scholar 

  32. 32.

    Gualtieri CT, Morgan DW. The frequency of cognitive impairment in patients with anxiety, depression, and bipolar disorder: an unaccounted source of variance in clinical trials. J Clin Psychiatry. 2008;69(7):1122–30.

    PubMed  Google Scholar 

  33. 33.

    Lam RW, Iverson GL, Evans VC, Yatham LN, Stewart K, Tam EM, et al. The effects of desvenlafaxine on neurocognitive and work functioning in employed outpatients with major depressive disorder. J Affect Disord. 2016;203:55–61.

    CAS  PubMed  Google Scholar 

  34. 34.

    Field A. Discovering statistics using SPSS. 3rd ed. Thousand Oaks: SAGE Publications Ltd; 2009.

    Google Scholar 

  35. 35.

    Cohen J. Statistical power analysis for the behavioral sciences. Abingdon: Routledge; 1988.

    Google Scholar 

  36. 36.

    Morris SB, DeShon RP. Combining effect size estimates in meta-analysis with repeated measures and independent-groups designs. Psychol Methods. 2002;7(1):105–25.

    PubMed  Google Scholar 

  37. 37.

    Singer JDWJ. Applied longitudinal data analysis: modeling change and event occurrence. Oxford: Oxford University Press; 2003.

    Google Scholar 

  38. 38.

    Herrera-Guzman I, Gudayol-Ferre E, Herrera-Guzman D, Guardia-Olmos J, Hinojosa-Calvo E, Herrera-Abarca JE. Effects of selective serotonin reuptake and dual serotonergic-noradrenergic reuptake treatments on memory and mental processing speed in patients with major depressive disorder. J Psychiatr Res. 2009;43(9):855–63.

    PubMed  Google Scholar 

  39. 39.

    Burdick KE, Russo M, Frangou S, Mahon K, Braga RJ, Shanahan M, et al. Empirical evidence for discrete neurocognitive subgroups in bipolar disorder: clinical implications. Psychol Med. 2014;44(14):3083–96.

    CAS  PubMed  PubMed Central  Google Scholar 

  40. 40.

    Chakrabarty TTI, Su WW, Sawatzky R, Keramatian K, Yatham LN. Cognitive subgroups in first episode bipolar I disorder: relation to clinical and brain volumetric variables. Acta Psychiatr Scand. 2020;143:151–61.

    PubMed  Google Scholar 

  41. 41.

    Martin DM, Wollny-Huttarsch D, Nikolin S, McClintock SM, Alonzo A, Lisanby SH, et al. Neurocognitive subgroups in major depressive disorder. Neuropsychology. 2020;34(6):726–34.

    PubMed  Google Scholar 

  42. 42.

    Bennabi D, Haffen E, Van Waes V. Vortioxetine for cognitive enhancement in major depression: from animal models to clinical research. Front Psychiatry. 2019;10:771.

    PubMed  PubMed Central  Google Scholar 

  43. 43.

    Harmer CJ. Emotional processing and antidepressant action. Curr Top Behav Neurosci. 2013;14:209–22.

    CAS  PubMed  Google Scholar 

  44. 44.

    Ma Y. Neuropsychological mechanism underlying antidepressant effect: a systematic meta-analysis. Mol Psychiatry. 2015;20(3):311–9.

    CAS  PubMed  Google Scholar 

  45. 45.

    Enneking V, Leehr EJ, Dannlowski U, Redlich R. Brain structural effects of treatments for depression and biomarkers of response: a systematic review of neuroimaging studies. Psychol Med. 2020;50(2):187–209.

    PubMed  Google Scholar 

  46. 46.

    Stahl SM. Stahl’s essential psychopharmacology: neuroscientific basis and practical applications. 4th ed. New York: Cambridge University Press; 2013.

    Google Scholar 

  47. 47.

    Amalric M, Koob GF. Depletion of dopamine in the caudate nucleus but not in nucleus accumbens impairs reaction-time performance in rats. J Neurosci. 1987;7(7):2129–34.

    CAS  PubMed  PubMed Central  Google Scholar 

  48. 48.

    Howes OD, Williams M, Ibrahim K, Leung G, Egerton A, McGuire PK, et al. Midbrain dopamine function in schizophrenia and depression: a post-mortem and positron emission tomographic imaging study. Brain. 2013;136(Pt 11):3242–51.

    PubMed  PubMed Central  Google Scholar 

Download references

Author information

Affiliations

Authors

Consortia

Corresponding author

Correspondence to Trisha Chakrabarty.

Ethics declarations

Funding

CAN-BIND is an Integrated Discovery Program carried out in partnership with, and financial support from, the Ontario Brain Institute [grant title “Canadian Biomarker Integration Network for Depression (CAN-BIND)”], an independent non-profit corporation, funded partially by the Ontario government. The opinions, results, and conclusions are those of the authors and no endorsement by the Ontario Brain Institute is intended or should be inferred. Additional funding was provided by CIHR, Lundbeck, Bristol-Myers Squibb, Pfizer and Servier. Funding and/or in kind support is also provided by the investigators’ universities and academic institutions. All study medications are independently purchased at wholesale market values.

Conflict of interest

Trisha Chakrabarty has received grant funding from the Michael Smith Foundation for Health Research and the National Research Council Canada. Shane J. McInerney has received advisory panel income from Janssen and research grant funding through the Healthy Minds Canada/Pfizer Canada Workplace Depression Awards. Ivan J. Torres has received consulting fees or sat on advisory boards for Lundbeck Canada, Sumitomo Dainippon and Community Living British Columbia. Benicio N. Frey has received research grants from Pfizer. Roumen V. Milev has received honoraria for ad hoc speaking or advising/consulting or received research funds from Lundbeck, Kye, Shire, Sunovion, Janssen, Lallemand, Allergan, Otsuka, Canadian Institutes of Health Research, Canadian Biomarker Integration Network for Depression, Ontario Brain Institute and Ontario Mental Health Foundation. Daniel J. Müller has received research funds from the Centre for Addiction and Mental Health Foundation, Canadian Institutes of Health Research and the National Institute of Health. Susan Rotzinger holds a patent “Teneurin C-Terminal Associated Peptides (TCAP) and methods and uses thereof. Inventors: David Lovejoy, R.B. Chewpoy, Dalia Barsyte, Susan Rotzinger.” Sidney H. Kennedy has received research funding or honoraria from the following sources: Abbott, Alkermes, Allergan, Boehringer lngelheim, Brain Canada, Canadian Institutes for Health Research, Janssen, Lundbeck, Lundbeck Institute, Ontario Brain Institute, Ontario Research Fund, Otsuka, Pfizer, Sanofi, Servier, Sunovion and Xian-Janssen. Sidney H. Kennedy holds stock in Field Trip Health. Raymond W. Lam has received honoraria for ad hoc speaking or advising/consulting, or received research funds from Akili, Allergan, Asia-Pacific Economic Cooperation, BC Leading Edge Foundation, Brain Canada, Canadian Institutes of Health Research, Canadian Network for Mood and Anxiety Treatments, Canadian Psychiatric Association, CME Institute, Hansoh, Janssen, Lundbeck, Lundbeck Institute, Medscape, Mind Mental Health Technologies, Otsuka, Pfizer, St. Jude Medical, University Health Network Foundation and Vancouver General Hospital Foundation.

Ethics approval

The authors assert that all procedures contributing to this work comply with the ethical standards of the relevant national and institutional committees on human experimentation and with the Helsinki Declaration of 1964, as revised in 2008. All procedures were approved by individual institutional research ethics boards.

Consent to participate

All participants provided written informed consent and received compensation for participation.

Consent for publication

All participants signed informed consent regarding publishing their data.

Data availability

The datasets generated during and/or analysed during the current study are not publicly available, but may be available on reasonable request upon permission by the CAN-BIND Investigator’s Team and Ontario Brain Institute. Syntax used for data analysis in SPSS are available upon reasonable request.

Author contributions

All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by TC, SJM, IJT, BNF, RVM, DJM, SR, SHK and RWL. The first draft of the manuscript was written by TC and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (DOCX 776 KB)

Supplementary file2 (DOCX 68 KB)

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Chakrabarty, T., McInerney, S.J., Torres, I.J. et al. Cognitive Outcomes with Sequential Escitalopram Monotherapy and Adjunctive Aripiprazole Treatment in Major Depressive Disorder: A Canadian Biomarker Integration Network in Depression (CAN-BIND-1) Report. CNS Drugs 35, 291–304 (2021). https://doi.org/10.1007/s40263-021-00793-1

Download citation