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



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.


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


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.


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.


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. identifier

NCT01655706; 2 August, 2012.

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Corresponding author

Correspondence to Trisha Chakrabarty.

Ethics declarations


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.

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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.

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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).

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