La Cognition Et Son Association Avec Le Fonctionnement Psychosocial Et Professionnel Durant Le Traitement Par Escitalopram Chez Des Patients Souffrant De Trouble Dépressif Majeur: Une Étude Can-Bind-1
The Canadian Journal of Psychiatry /La Revue Canadienne de Psychiatrie2021, Vol. 66(9) 798–806© The Author(s) 2020Article reuse guidelines:sagepub.com/journals-permissionsDOI: 10.1177/0706743720974823TheCJP.ca | LaRCP.ca
Objectives: Major depressive disorder (MDD) is associated with impairments in both cognition and functioning. However, whether cognitive deficits significantly contribute to impaired psychosocial and occupational functioning, independent of other depressive symptoms, is not well established. We examined the relationship between cognitive performance and functioning in depressed patients before and after antidepressant treatment using secondary data from the first Canadian Biomarker Integration Network in Depression-1 study.
Methods: Cognition was assessed at baseline in unmedicated, depressed participants with MDD (n = 207) using the Central Nervous System Vital Signs computerized battery, psychosocial functioning with the Sheehan Disability Scale (SDS), and occupational functioning with the Lam Employment Absence and Productivity Scale (LEAPS). Cognition (n = 181), SDS (n = 175), and LEAPS (n = 118) were reassessed after participants received 8 weeks of open-label escitalopram monotherapy. A series of linear regressions were conducted to determine (1) whether cognitive functioning was associated with psychosocial and occupational functioning prior to treatment, after adjusting for overall depressive symptom severity and (2) whether changes in cognitive functioning after an 8-week treatment phase were associated with changes in psychosocial and occupational functioning, after adjusting for changes in overall symptom severity.
Results: Baseline global cognitive functioning, after adjusting for depression symptom severity and demographic variables, was associated with the SDS work/study subscale (β = −0.17; P = 0.03) and LEAPS productivity subscale (β = −0.17; P = 0.05), but not SDS total (β = 0.19; P = 0.12) or LEAPS total (β = 0.41; P = 0.17) scores. Although LEAPS and SDS scores showed significant improvements after 8 weeks of treatment (P < 0.001), there were no significant associations between changes in cognitive domain scores and functional improvements.
Conclusion: Cognition was associated with occupational functioning at baseline, but changes in cognition were not associated with psychosocial or occupational functional improvements following escitalopram treatment. We recommend the use of more comprehensive functional assessments to determine the impact of cognitive change on functional outcomes in future research.
Objectifs : Le trouble dépressif majeur (TDM) est associé à des déficiences de la cognition et du fonctionnement. Toutefois, il n’est pas bien établi que des déficits cognitifs contribuent significativement au fonctionnement psychosocial et professionnel altéré, indépendamment d’autres symptômes dépressifs. Nous avons examiné la relation entre le rendement cognitif et le fonctionnement chez les patients déprimés avant et après le traitement par antidépresseur à l’aide des données secondaires de la première étude du Réseau canadien d’intégration des biomarqueurs pour la dépression (CAN-BIND-1).
Méthodes : La cognition a été évaluée au départ chez des participants déprimés, non médicamentés et souffrant de TDM (n = 207) à l’aide d’une batterie informatisée des signes vitaux du système nerveux central (SV-SNC), le fonctionnement psychosocial avec l’échelle d’invalidité de Sheehan (SDS) et le fonctionnement professionnel grâce à l’échelle d’absence d’emploi et de productivité de Lam (LEAPS). La cognition (n = 181), la SDS (n = 175), et la LEAPS (n = 118) ont été réévaluées après que les participants ont reçu 8 semaines de monothérapie ouverte d’escitalopram.
Une série de régressions linéaires a été menée afin de déterminer : 1) si le fonctionnement cognitif était associé au fonctionnement psychosocial et professionnel avant le traitement, après ajustement pour la gravité des symptômes dépressifs en général, et 2) si les changements du fonctionnement cognitif après une phase de 8 semaines de traitement étaient associés aux changements du fonctionnement psychosocial et professionnel, après ajustement pour les changements de la gravité des symptômes dépressifs en général.
Résultats : Le fonctionnement cognitif général au départ, après ajustement pour la gravité des symptômes dépressifs et les variables démographiques, était associé à la sous-échelle SDS de l’étude (ß = -0,17; p = 0,03) et à la sous-échelle de productivité LEAPS (ß = -0,17; p = 0,05), mais pas au total des scores de la SDS (ß = 0,19; p = 0,12) ni au total des scores de la LEAPS (ß = 0,41; p = 0,17). Bien que les scores à la LEAPS et à la SDS aient affiché des améliorations significatives après 8 semaines de traitement (p < 0,001), il n’y avait pas d’associations significatives entre les changements des scores du domaine cognitif et les améliorations fonctionnelles.
Conclusion : La cognition était associée au fonctionnement professionnel au départ, mais les changements de la cognition n’étaient pas associés aux améliorations du fonctionnement psychosocial ou professionnel à la suite du traitement par escitalopram. Nous recommandons à la future recherche d’utiliser des évaluations fonctionnelles plus exhaustives afin de déterminer l’effet du changement cognitif sur les résultats fonctionnels.
cognition, depression, functional outcomes, antidepressant treatment
According to the Global Burden of Disease Study 2017, depressive disorders are one of the leading causes of disability worldwide.1 Major depressive disorder (MDD) has an average annual prevalence of 5.5% in Canada and has a significant impact on psychosocial functioning and work productivity.2,3 MDD is also characterized by objectively measured cognitive deficits, with meta-analyses finding moderate deficits in the cognitive domains of memory, attention, and executive function relative to healthy participants.4-8 These deficits are detectable during acute major depressive episodes (MDE) and during symptom remission, indicating that cognitive dysfunction in MDD is partially separable from overall depressive symptom severity. However, while it has been established that MDD is associated with both cognitive deficits and functional disability, it remains unclear if cognitive dysfunction is independently associated with functional impairment in MDD. Some studies have identified cognition as a key mediator of psychosocial and occupational functioning in MDD patients independent of overall depression symptom severity,9,10 while others have found no such relationships.11-13
In addition to clarifying whether cognition is associated cross-sectionally with functioning, it is unclear if treatmentrelated changes in cognition are related to functional improvements, independent of changes in overall symptom severity. This question has important therapeutic implications, as the presence of such an association would indicate that cognition should be a priority treatment target to facilitate functional recovery in individuals with MDD. While antidepressant treatment has been associated with modest but significant improvements in a number of cognitive domains such as processing speed, memory, and attention,14 few longitudinal studies have examined the association between treatment-related changes in cognition and functional improvements in MDD,6 and those that have been conducted have yielded inconsistent results. In an open-label study of MDD participants who were treated with vortioxetine, improvements in working memory, executive function, attention, and processing speed were associated with improvements in functioning after 8 weeks of treatment.15 However, there was no significant association between objectively measured cognition and occupational functioning after accounting for changes in depression symptom severity in a 52-week open-label vortioxetine study.16 However, this study used only 1 test, the digit symbol substitution test (DSST), to objectively assess cognition. This highlights the need to evaluate the relationship between changes in objective cognitive functioning and functional improvements using a comprehensive multidomain cognitive battery.
To address these questions, we examined the association between cognitive performance and psychosocial/occupational functioning in MDD. This was a secondary analysis of data from a multicentre study of predictive biomarkers for antidepressant response, which involved repeated administration of a comprehensive cognitive battery and measures of psychosocial and occupational functioning.17,18 We hypothesized that (1) cognitive functioning would be positively associated with psychosocial and occupational functioning at baseline, independent of baseline depressive symptom severity and (2) improvements in cognitive functioning would be associated with improvements in psychosocial and occupational functioning after 8 weeks of antidepressant treatment, independent of improvements in overall symptom severity. Elucidating these cognitive-functional associations will help clarify the importance of cognition as an independent therapeutic target for individuals with MDD.
Participants were recruited as part of the first Canadian Biomarker Integration Network in Depression (CAN-BIND-1) trial from 6 research centres across Canada as per the published CAN-BIND protocol.18 Research ethics board approval was obtained from each site, and participants provided written informed consent. Briefly, eligible participants were required to meet the following inclusion criteria: (1) outpatients age 18 to 60 years, (2) Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision criteria for an MDE in MDD, as determined using the Mini- International Neuropsychiatric Interview,19 (3) MDE duration of ≥3 months, (4) free of psychotropic medications for a minimum of 5 half-lives, (5) Montgomery–Asberg Depression Rating Scale (MADRS) ≥ 24,20 and (6) fluent enough in English to complete interviews and self-report questionnaires. Criteria for exclusion included bipolarity, any other psychiatric disorder as the primary diagnosis, high suicide risk, substance abuse, medical instability, failure of symptom improvement with 4 or more adequate pharmacological interventions, recent commencement of psychological therapy, and previous failure of symptom improvement or intolerance to escitalopram or aripiprazole. The complete list of inclusion and exclusion criteria is outlined in the published CAN-BIND protocol paper.18
Following baseline assessment, MDD participants were initiated on open-label escitalopram 10 mg daily, increasing to 20 mg daily at week 2 or 4 based on clinician judgment of effectiveness/tolerability. Responders (those showing a ≥50% reduction in MADRS scores from baseline) at 8 weeks continued on the effective dose of escitalopram, while nonresponders were treated with adjunctive aripiprazole for an additional 8 weeks. This report focuses on data from the initial 8-week escitalopram monotherapy phase, and the additional 8-week data will be examined in a subsequent paper.
Demographic information was collected at baseline. Clinical, cognitive, and functional assessments were completed at baseline and week 8 (Figure 1). The main clinical outcome measure was the MADRS, assessing depression symptom severity. Functioning was assessed using the Sheehan Disability Scale (SDS) and the Lam Employment Absence and Productivity Scale (LEAPS).21,22
The SDS is a measure of functional disability and impairment and is comprised of 3 self-rated items, relating to family, work, and social impairment. Each participant was asked to rate on a scale of 0 to 10 (with 0 meaning “not at all” and 10 meaning “extremely”) how much their symptoms have disrupted (a) work/school (SDS work/school), (b) social life/leisure activities (SDS social), and (c) family life/home responsibilities (SDS family/home). A total SDS psychosocial disability score (maximum score of 30) and the 3 individual subscale scores were used for analysis.
The LEAPS is a measure of impairment in occupational functioning, specifically developed for use in employed, clinically depressed populations. Participants rate how often they have been bothered by 7 common depression-related symptoms and impairments (e.g., poor concentration or memory, low energy, getting less work done) over the past 2 weeks. The 7 items are rated on 5-point Likert-type scale of frequency (0 = “none of the time” to 4 = “all of the time”). LEAPS total scores range from 0 (no impairment) to 28 (extreme impairment). A productivity subscale measure based on 3 items of the LEAPS (getting less work done, doing poor quality work, and making more mistakes) was also used, with higher scores indicating greater work impairment. Only those in paid employment completed this questionnaire.
The Central Nervous System Vital Signs (CNS-VS) computerized battery has been validated to detect cognitive deficits in mood disorders and was used to assess cognitive performance at baseline and week 8.23,24 The CNS-VS produces a neurocognitive index (NCI) score, a measure of global cognition, based on the average of 5 domain scores: composite memory (a composite of verbal and visual memory), psychomotor speed, reaction time, cognitive flexibility, and complex attention. Performance on each of these 5 domains was used for secondary analysis. Raw scores for all domains were automatically transformed into standard scores based on an age-matched normative sample, in which domain scores have a mean of 100 and standard deviation (SD) of 15. Objective “validity indicators” are generated by CNS-VS to flag low scores due to poor effort or misunderstanding instructions. Invalid scores were discarded, and outliers greater than 4 SDs were capped as per previously described protocols.25
Statistical analyses were carried out using SPSS Version 24.0 and all statistical tests were 2-tailed.26 Descriptive statistics were calculated for the participant groups’ age, gender, years of education, and other clinical variables. We applied the paired Wilcoxon test to assess whether there were significant changes in symptom severity (using the MADRS), cognition, and functioning from baseline to week 8.
To assess the association between cognition and functioning at baseline, linear regression analysis using baseline NCI scores as the main predictor variable and measures of baseline functioning as the outcome variables was conducted. Covariates potentially associated with functioning (age, sex, years of education, and baseline MADRS score) were inserted into the first step of regression models followed by baseline NCI scores in the second step. Measures of baseline functioning used as outcome variables were the psychosocial functional measures—SDS total score, SDS subscales (SDS work/school, SDS social, and SDS family/home) and occupational functioning measures—LEAPS total score and LEAPS productivity score.
As a secondary analysis, exploratory regression analyses were conducted if a statistically significant association between NCI and a functional outcome variable was identified. The aim of this step was to investigate whether any individual cognitive domain(s) was significantly associated with functional outcomes. In this analysis, covariates were added in the first step as described above, followed by each individual cognitive domain score (memory, psychomotor speed, reaction time, cognitive flexibility, and complex attention). As we were testing for prespecified hypotheses that cognitive scores would be associated with functioning and to prevent type I error, which may result from stringent correction for multiple comparisons, we retained a significance level of P < 0.05.27
To assess the association between changes in cognition and functioning over the treatment course, we conducted linear regression analysis with change in NCI score from baseline to week 8 as the main predictor variable and change in functional scores from baseline to week 8 as the outcome variables. Age, sex, years of education, and baseline to week 8 change in MADRS score were added as covariates in the first step of regression analyses, and change in NCI scores added in the second step. Significant associations between change in NCI scores and changes in functional scores were followed up with regressions using changes in individual cognitive domain scores as predictor variables. For all regression models, normality of residuals was assessed and confirmed by plotting qq plots.
A total of 207 MDD participants completed both the baseline visit and the CNS-VS cognitive assessment battery. Some participants (55.9%) were being treated with antidepressant at screening assessment (see Table 1), and all had their treatment discontinued for a minimum of 5 half-lives before the study commenced. A total of 171 participants completed 8 weeks of escitalopram treatment and the CNS-VS at week 8. The demographic and clinical characteristics of this sample are presented in Table 1. The majority of the sample was female (N = 130, 62.8%), employed (N = 135, 65.2%), had a mean age of 35, and had 14 years of education. At baseline, LEAPS was completed by 135 actively employed participants and by 118 (87.4%) at week 8. Two hundred and two participants completed baseline SDS, of whom 175 (86.6%) completed week 8 SDS (see Figure 1).
Overall, there was a significant improvement on the MADRS, LEAPS, and SDS scores between baseline and 8 weeks of treatment and an overall statistically significant increase in NCI and all cognitive domain scores after 8 weeks of treatment (see Table 1).
Depression symptom severity was associated with all baseline functional variables in the first step of regression analyses. Specifically, baseline MADRS scores were significantly associated with SDS total score (β = 0.19, P = 0.01, adjusted R2 = 0.04) and LEAPS total score (β = 0.41, P < 0.001, adjusted R2 = 0.12; Table 2). MADRS score was positively (i.e., higher depression symptom severity associated with greater functional impairments) associated with SDS work/school (β = 0.25, P = 0.002, adjusted R2 = 0.04), SDS social (β = 0.19, P = 0.007, adjusted R2 = 0.02), SDS family/home (β = 0.18, P = 0.01, adjusted R2 = 0.06), and LEAPS productivity subscale (β = 0.36, P = 0.0001, adjusted R2 = 0.12).
There was no association between baseline NCI scores and baseline SDS total score or LEAPS total score, after adjusting for age, sex, and MADRS scores (Table 2). Baseline NCI scores were negatively associated (i.e., lower NCI with greater functional impairment) with SDS work/school subscale (β = −0.17, P = 0.03, adjusted R2 = 0.07) and LEAPS productivity subscale scores (β = −0.17, P = 0.05, adjusted R2 = 0.13; Table 3).
In the secondary analysis, we investigated the relationship between individual cognitive domains, SDS work/school subscale, and LEAPs productivity subscale scores. For LEAPS productivity, there was a significant association with reaction time (β = −0.19, P = 0.02, adjusted R2 = 0.15) and cognitive flexibility (β = −0.17, P = 0.05, adjusted R2 = 0.13), after adjusting for age, sex, education, and baseline MADRS (Supplemental Table 1). Associations were also found between SDS work/school with psychomotor speed (β = −0.16, P = 0.04, adjusted R2 = 0.06) and memory (β = −0.20, P = 0.01, adjusted R2 = 0.08; Supplemental Table 2).
In the first step of regression analyses, decreased MADRS scores were significantly associated with decreases (i.e., functional improvements) in SDS total score (β = 0.42, P < 0.001, adjusted R2 = 0.26) and LEAPS total score (β = 0.54, P < 0.001, adjusted R2 = 0.36) (Table 4). Decreased MADRS scores also showed highly significant associations with improvement in SDS work/school (β = 0.38, P = 0.0001, adjusted R2 = 0.14), SDS social (β = 0.41, P = 0.0001, adjusted R2 = 0.25), SDS family/home (β = 0.41, P = 0.0001, adjusted R2 = 0.21), and LEAPS productivity subscale (standardized β = 0.28, P = 0.0001, adjusted R2 = 0.28).
Change in NCI score was not associated with change in total LEAPS or SDS score after controlling for age, gender, education, and change in MADRS scores (Table 4). A nonsignificant trend was found for changes in LEAPS productivity (β = −0.16, P = 0.07, adjusted R2 = 0.29; Supplemental Table 3). As there were no associations between NCI and functional scores, no secondary analyses were performed.
This study aimed to explore the relationships between cognitive performance and functional outcomes in MDD, and whether changes in cognition were associated with changes in psychosocial functioning following antidepressant treatment. As previously reported,17 participants with MDD experienced an overall improvement in depressive symptoms and functioning after 8 weeks of treatment with escitalopram. However, we also found that higher depression symptom severity was associated with decreased overall psychosocial and occupational functioning, as assessed by SDS and LEAPS total scores. Baseline global cognitive performance, assessed with the NCI, was not associated with total scores on these scales after controlling for overall symptom severity. Instead, baseline NCI scores were associated with occupational impairment subscales (SDS work/school item and LEAPS productivity subscale), indicating that lower cognitive performance was associated with greater occupational impairments. Memory, cognitive flexibility, reaction time, and psychomotor speed were the individual cognitive domains, which were significantly associated with occupational functioning. These associations were present after adjusting for baseline depression symptom severity, indicating that cognitive performance contributes to occupational functioning independent of depressive symptom severity. These results also suggest that cognitive deficits may specifically impact occupational, rather than social or home functioning.
Some studies have found significant associations between cognition and functioning in acute MDD,11,28,29 while others have not.12,13 Our study generally supports the body of knowledge that there is a relationship between baseline cognition and functioning in MDD populations. However, our second hypothesis, that changes in cognition following antidepressant treatment would be associated with improved functional outcomes, was not supported. While functioning significantly improved after treatment, our regression analysis did not find that functional improvement was associated with cognitive changes after adjusting for improvement in overall symptom severity. Improved functioning at follow-up appears to be more related to improvement in severity of depression than specifically to cognitive improvement.
This lack of relationship has been found in previous studies15,16 after correcting for relevant demographic and clinical variables. These results suggest that the relationship between functioning and cognition in individuals with MDD may be more complex than originally hypothesized, and there may be other factors independently affecting cognition and functioning. Chokka et al. reported that subjectively evaluated cognitive complaints in patients with MDD are associated with functioning both cross-sectionally and longitudinally, while no such association was found with objective cognitive performance (assessed via the DSST).16 Lack of concordance between subjectively and objectively measured cognitive functioning is a well-replicated finding in MDD and may be due to negatively biased self-appraisal of performance.30 Thus, changes in subjective cognitive measures and affectively influenced cognitive functioning (i.e., “hot” cognition) may show greater associations with changes in overall functioning compared to objective “cold” cognitive tests.
There are some limitations to our study. First, this is an open-label study, which means that some of the positive effects observed in our sample may have been due to nonspecific effects instead of the medication. Second, not all patients completed all visits, leading to some missing data, which may have affected our results. Third, the observed improvements in cognitive performance may have been partly due to practice effects. Other factors besides pharmacological treatment, such as lifestyle changes or major life events, not assessed in this study may also have accounted for improvements observed in cognition and functioning. A fourth limitation was that although the SDS and LEAPS are well validated, they are self-rated and brief (3–7 items) measures of psychosocial functioning. It is possible that relationships between cognition and functioning may be more apparent with use of more comprehensive- or performance-based functional measures. Another limitation was that while CNS-VS was designed for serial administrations by the inclusion of alternate versions of tasks, practice effects may still have contributed to some degree to the observed improvements in cognition. Finally, this article only analyzed data at the 8-week follow-up. Future analyses will examine an additional 8 weeks of treatment, where the longer term effects of escitalopram and the addition of aripiprazole to escitalopram nonresponders will be explored.
In conclusion, cognitive functioning was significantly associated with baseline occupational functioning but not overall psychosocial functioning in this sample of participants with MDD. While 8 weeks of escitalopram treatment were shown to improve psychosocial and occupational functioning, we did not find associations between changes in cognition and functional improvements. Further studies are required to investigate the mediators of functional improvement with specific antidepressants and other treatments in MDD.
The data for this study are not yet publicly available. It will be available through the Ontario Brain Institute BrainCODE platform in the future.
The authors would like to acknowledge Sophia Vaccarino and Keith Ho for their assistance with preparation of the cognition and functional outcome data. The opinions, results, and conclusions are those of the authors, and no endorsement by the Ontario Brain Institute is intended or should be inferred.
The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: S.J.M. has received consulting honoraria from Janssen. R.V.M. has received consulting and speaking honoraria from Allergan, Janssen, KYE, Lundbeck, Otsuka, Pfizer, and Sunovion and research grants from Janssen, Lallemand, Lundbeck, Nubiyota, and Pfizer. B.N.F. reports a research grant from Pfizer. S.H.K. has received research funding or honoraria from Abbott, Alkermes, Allergan, BMS, Janssen, Lundbeck, Lundbeck Institute, Otsuka, Pfizer, Servier, Sunovion, and Xian-Janssen. S.R. reports grants from Ontario Brain Institute during the conduct of the study. S.R. also has a patent Teneurin C-terminal associated peptides and uses thereof issued. R.W.L. has received speaking and consulting honoraria and/or research grants from Allergan, Asia-Pacific Economic Cooperation, BC Leading Edge Foundation, Canadian Institutes of Health Research (CIHR), Canadian Network for Mood and Anxiety Treatments (CANMAT), Canadian Psychiatric Association, Hansoh, Healthy Minds Canada, Janssen, Lundbeck, Lundbeck Institute, MITACS, Myriad Neuroscience, Ontario Brain Institute, Otsuka, Pfizer, St. Jude Medical, University Health Network Foundation, and VGH-UBCH Foundation. M.M., G.M.Q., A.V.R., and T.C. list no competing interests.
The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: Canadian Biomarker Integration Network in Depression is an Integrated Discovery Program carried out in partnership with, and financial support from, the Ontario Brain Institute, an independent nonprofit corporation, funded partially by the Ontario government. Additional funding is provided by the Canadian Institutes of Health Research, 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.
Shane J. McInerney, MD, MSc https://orcid.org/0000-0003-1062-6464
Glenda M. MacQueen, MD, PhD https://orcid.org/0000-0003-3352-6781
Arun V. Ravindran, MD https://orcid.org/0000-0002-1655-2753
Raymond W. Lam, MD https://orcid.org/0000-0001-7142-4669
The supplemental material is available in the online version of the article.
1 Department of Psychiatry, University of Toronto, Ontario, Canada
2 Department of Psychiatry, University Hospital Galway, Ireland
3 Department of Psychiatry, University of British Columbia, Vancouver, British Columbia, Canada
4 Centre for Addiction and Mental Health, Campbell Family Mental Health Research Institute, Toronto, Ontario, Canada
5 Department of Rheumatology, Center of Experimental Rheumatology, University Hospital Zurich, Switzerland
6 Department of Psychiatry and Behavioural Neurosciences, McMaster University, Hamilton, Ontario, Canada
7 Department of Psychiatry, Queen’s University, Kingston, Ontario, Canada
8 Department of Psychology, Queen’s University, Kingston, Ontario, Canada
† Deceased, formerly Department of Psychiatry, University of Calgary, Calgary, Alberta, Canada.
Corresponding Author:Shane J. McInerney, MD, MSc, Department of Psychiatry, National University of Ireland, Galway, Ireland.Email: shane.mcinerney1@hse.ie
