The clinical relationship between cognitive impairment and psychosocial functioning in major depressive disorder: A systematic review

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The Clinical Relationship Between Cognitive Impairment and Psychosocial Functioning in Major Depressive Disorder: A Systematic Review Olivia R. Cambridge , Matthew J. Knight , Natalie Mills , Bernhard T. Baune PII: DOI: Reference:

S0165-1781(18)30307-X https://doi.org/10.1016/j.psychres.2018.08.033 PSY 11627

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Psychiatry Research

Received date: Revised date: Accepted date:

26 February 2018 12 August 2018 12 August 2018

Please cite this article as: Olivia R. Cambridge , Matthew J. Knight , Natalie Mills , Bernhard T. Baune , The Clinical Relationship Between Cognitive Impairment and Psychosocial Functioning in Major Depressive Disorder: A Systematic Review, Psychiatry Research (2018), doi: https://doi.org/10.1016/j.psychres.2018.08.033

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Highlights  Deficits in several cognitive domains predicts disability in quality of life, and social, occupational, and global functioning  Self-perceived daily functioning is primarily associated with executive functioning and global cognition  Longitudinal psychosocial functioning outcomes are related to executive functioning, attention, and memory  Older age and greater depression symptom severity appear to enhance the negative relationship between cognitive deficits on psychosocial functioning

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The Clinical Relationship Between Cognitive Impairment and Psychosocial Functioning in Major Depressive Disorder: A Systematic Review

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#Olivia R. Cambridge(Hons), #Matthew J. Knight(PhD), Natalie Mills(MBBS, PhD), Bernhard T. Baune(Prof)*

The University of Adelaide, Adelaide Medical School, Discipline of Psychiatry, Adelaide,

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Australia

#These authors contributed equally to this work and are regarded as first authors

Corresponding author

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Bernhard T. Baune

University of Adelaide Level 7

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Adelaide Medical School

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Health and Medical Sciences Building North Terrace Adelaide, SA 5000

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AUSTRALIA

[email protected]

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Ph: +61883137382

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ACCEPTED MANUSCRIPT 1. INTRODUCTION

A well-established body of research suggests that cognitive dysfunction accompanies psychiatric disorders including Major Depressive Disorder (MDD), with impaired ability to think, concentrate and make decisions appearing in the diagnostic criteria (American Psychiatric Association, 2013). While the association between cognitive dysfunction and functional deficits in everyday life has been thoroughly explored in schizophrenia and Bipolar (Martínez-Arán et al., 2004; Thomas et al., 2004)),

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this relationship requires further investigation in MDD (Knight and Baune, 2018a; McIntyre et al., 2015; Rock et al., 2014a). Recent literature conceptualizes functional issues within the umbrella term “Psychosocial Functioning”, which can be broadly understood as the degree to which individuals successfully interact with their environment across in daily, occupational, and social domains (Ro

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and Clark, 2009), as well as self-perceived quality of life (Evans et al., 2014).

Recent studies have identified that clinical features influence cognitive dysfunction in MDD, including depression severity (McDermott and Ebmeier, 2009), age of onset (Thomas et al., 2009; Wekking et al., 2012), education (Beblo et al., 2011), psychiatric comorbidity (Baune et al., 2009), premorbid IQ and illness duration (Elgamal et al., 2010). However, very little is known regarding the

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extent to which these factors influence the relationship between cognitive impairment and psychosocial dysfunction in the short or long-term. Given that cognitive and psychosocial

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impairments have been found to persist beyond the acute stage of depression, it is crucial to identify whether specific clinical subgroups (e.g., the elderly) are more vulnerable to functional deficits

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associated with cognitive dysfunction (Baune et al., 2010; Hasselbalch et al., 2011; Rock et al., 2014b).

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A previous review of cognition and psychosocial function in MDD by Evans et al. (2014) identified very few studies of this field (N= 10), as well as significant methodological limitations which

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restricted definitive conclusions. As a result, it is not currently known which cognitive domains are the strongest predictors of psychosocial dysfunction. In addition, there is no consensus regarding the persistence of cognitive and psychosocial dysfunction over the long-term course of illness, or the degree to which other illness factors (e.g., age) influence the cognition-psychosocial functioning relationship. This review addresses these important gaps in our understanding by evaluating studies of the relationship between cognition and psychosocial functioning in MDD.

1.2 Objectives

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ACCEPTED MANUSCRIPT The overarching aim of this systematic review was to examine studies of the relationship between cognitive and psychosocial function in adults with MDD. The primary goals were to identify: (1) Which cognitive domains are the strongest predictors of performance-based and subjectively evaluated psychosocial functioning? (2) Are cognitive deficits associated with psychosocial dysfunction in the long-term course of illness? (3) Which clinical and demographic characteristics influence the relationship between cognitive and

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psychosocial dysfunction in MDD?

2. METHODS

2.1 Review Protocol

The literature search for this review was carried out according to the PRISMA (preferred reporting

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items for systematic review and meta-analyses) guidelines as they apply to systematic reviews (Liberati et al., 2009).

2.2 Information Sources

A systematic literature search was conducted using PubMed, PsychINFO, Scopus and Web of Science

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2.3 Search Strategy

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databases. Additional studies were identified through reference lists.

The following search terms were used (depression OR depressive disorder OR major depressive

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disorder OR major depression) AND combinations of (cognition OR cognitive OR neurocognitive OR neurocog*) with (dysfunction OR impairment OR function* OR disorder) AND (psychosocial function* OR social function OR daily function* OR quality of life OR activities of daily living OR social

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behavior OR executive function* OR neuropsychological tests). The following limits were applied: English language. A large number of search terms were included to capture the complexity of

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‘psychosocial functioning’, which is not used consistently in psychiatric literature.

2.4 Study Selection Process/Eligibility Criteria Studies were included if they met the inclusion criteria of (1) adults (>18 years of age) with a primary diagnosis of MDD by the Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSMIV), International Classification of Diseases, ninth or tenth revisions (ICD-9, ICD-10), the World Health Organisation Composite International Diagnostic Interview (CIDI) or the relevant cut off scores for the Center for Epidemiologic Studies Depression Scale (CES-D) and Geriatric Depression Scale (GDS)

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ACCEPTED MANUSCRIPT to indicate clinical depression; (2) use of cognitive tests; and (3) use of measures of measures of psychosocial functioning; (4) collection of original data. Studies were excluded if they included patients not meeting the criteria for MDD per the diagnostic tools above, or if they were not original studies. Studies were also excluded if they did not provide a test of the statistical significance of the relationship between cognition and psychosocial function. In total, 28 studies met these criteria (17 adult studies, 11 elderly studies).

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3. RESULTS

3.1 Study Selection

The systematic search process is shown in Figure 1. The initial search yielded 7271 articles

(PubMed=1428, PsychINFO=4149, Scopus=1689, Other=5). The relatively high number of articles

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was a result of the broad search terms used. Of these, 103 articles had titles or abstracts implying relevance for inclusion, the remaining 7168 were off topic and excluded. The 103 selected articles were examined by 1 reviewer. Articles were further excluded if they a) did not use a sample of MDD patients, b) did not include psychosocial assessments c) did not include cognitive tests, d) did not analyze the relationship between cognition and psychosocial functioning, or e) were not original

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studies (i.e., reviews or meta-analyses). Ten studies had been included in a previous review on the relationship between cognitive dysfunction and functional outcomes in adult major depression

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(Evans et al., 2014). There are no scrict criteria defining geriatric or elderly depression, so the use of an arbirtary age cut-off was avoided, thus there was some overlap in the age range of adult and

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elderly studies.

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Figure 1: Methods for Assessing Risk of Bias in Individual Studies

3.2 Study characteristics

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Table 1 (Adult studies) and Table 2 (Elderly studies) present cognitive and functional assessments employed, characteristics of the participant sample (e.g., sample size, mean age), and observed

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relationships between cognition and psychosocial functioning. A broad range of clinical and cognitive assessments were employed (Cotrena et al., 2016b; Daniel et al., 2013; Kim et al., 2016; McIntyre et

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al., 2015). Likewise, there was considerable variation in psychosocial functioning assessment tools

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(summarized in supplementary eTables 1 and 2).

Typical inclusion criteria for Adult studies was age (18 years), and a primary diagnosis of MDD as diagnosed by standard clinical interviews (e.g., the Mini International Neuropsychiatric Interview). Depression severity varied considerably, with two studies including remitted patients with low symptom scores (Baune et al., 2010; Shimizu et al., 2013) and two including severely depressed patients admitted to hospitals (McCall and Dunn, 2003; Withall et al., 2009). Eight adult studies included healthy controls or some form of normative control (Baune et al., 2010; Cotrena et al., 2016a; Cotrena et al., 2016b; Daniel et al., 2013; Godard et al., 2012; Naismith et al., 2007; Park et al., 2014; Shimizu et al., 2013). Most adult studies excluded patients with neurodegenerative or

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ACCEPTED MANUSCRIPT neurological disorders, brain or head injuries, learning disabilities, mental retardation or other conditions which can affect cognitive functioning. Five studies included patients with psychotic symptoms (Gildengers et al., 2012; Godard et al., 2012; Gupta et al., 2013; Jaeger et al., 2006; Mueser et al., 2010), whilst the remainder excluded these patients or did not report whether patients exhibited psychotic symptoms. Elderly studies (Table 2) included participants from 50 to 90 years of age, including participants with mild – severe depression, as well as healthy controls.

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Cross-sectional and longitudinal studies were examined independently, and results are presented by the domains of psychosocial functioning purportedly assessed in each study. Throughout all studies, we highlight whether any clinical factors (e.g., symptom severity) influence the relationship between cognition and psychosocial dysfunction. Presenting the results in this fashion facilitates examination of the factors relevant to the primary goals of this review; detection of (1) domain-specific and (2)

3.3 Cross-Sectional Studies 3.3.1 Self-Perceived Psychosocial Functioning 3.3.1.1 Quality of Life

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longitudinal cognition-psychosocial functioning relationships.

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Nine studies included a measure of Quality of life (QoL) in their analysis (Baune et al., 2010; Caldirola et al., 2014; Kamenov et al., 2016; Kim et al., 2016; McCall and Dunn, 2003; McIntyre et al., 2015;

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Naismith et al., 2007; Saragoussi et al., 2013; Shimizu et al., 2013) with all but two (Baune et al., 2010; Caldirola et al., 2014) finding a significant positive association with cognition. Quality of life was associated with delayed memory (McCall and Dunn, 2003), verbal recall (Shimizu et al., 2013),

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global cognition (Kamenov et al., 2016; McCall and Dunn, 2003) and self-rated cognitive deficits (Kim et al., 2016; McIntyre et al., 2015; Naismith et al., 2007; Saragoussi et al., 2013). Preliminary findings

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from a 2-year prospective study also reported that QoL was associated with cognitive dysfunction independently of depression severity (Saragoussi et al., 2013). Additionally, four studies also found

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that greater depression severity was associated with poor QoL (Kim et al., 2016; McCall and Dunn, 2003; McIntyre et al., 2015; Naismith et al., 2007; Shimizu et al., 2013).

3.3.1.2 Social and Interpersonal Functioning Five studies found that social functioning was positively related with cognitive ability (Cotrena et al., 2016a; Cotrena et al., 2016b; Godard et al., 2011; Gupta et al., 2013; McCall and Dunn, 2003). Performance in domains of attention (Cotrena et al., 2016a; Godard et al., 2011; Gupta et al., 2013), executive function (Godard et al., 2011), processing speed (Cotrena et al., 2016a; Cotrena et al., 2016b), verbal and delayed non-verbal memory (McCall and Dunn, 2003), inhibition (Cotrena et al.,

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ACCEPTED MANUSCRIPT 2016a), global cognition (McCall and Dunn, 2003) and cognitive flexibility (Cotrena et al., 2016a; Cotrena et al., 2016b) were all positively associated with social functioning. Conversely, two studies found no significant relationship between measures of social functioning and cognitive performance in a group of moderately-severely depressed inpatients (Caldirola et al., 2014) and mildly depressed outpatients (Shimizu et al., 2013).

3.3.1.3 Subjective Daily Functioning

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Two adult studies investigated the cross-sectional relationship between cognition and functioning (i.e., Activities of Daily Living (ADL)/Instrumental Activities of Daily Living (IADL)) (Baune et al., 2010; McCall and Dunn, 2003), with McCall and Dunn finding a positive association between cognitive and functional impairment (McCall and Dunn, 2003). This study investigated severely depressed

inpatients and found that higher Mini Mental State Exam (MMSE) scores of global cognition were

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related to better IADL performance in severely depressed patients. In contrast, a study by Baune et al. assessed both currently and previously moderately depressed outpatients and found that cognitive function was not related to impairments in ADL or IADL, excepting a marginal effect of attention on ADL performance (p= .06) (Baune et al., 2010).

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All seven cross-sectional elderly studies of daily dysfunction found an association with cognitive impairment (Gildengers et al., 2012; Kiosses and Alexopoulos, 2005; Kiosses et al., 2001; Mackin and

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Arean, 2009; Park et al., 2014; Tam and Lam, 2012; Wen et al., 2014). Cognitive domains related to daily functioning included executive function (Gildengers et al., 2012; Kiosses and Alexopoulos,

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2005; Kiosses et al., 2001; Mackin and Arean, 2009; Tam and Lam, 2012), attention (Mackin and Arean, 2009; Wen et al., 2014), delayed memory (Gildengers et al., 2012), verbal memory (Wen et al., 2014), global cognition (Gildengers et al., 2012; Park et al., 2014), language and visuomotor

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ability (Gildengers et al., 2012). Four studies reported an exacerbating effect of depression severity on cognitive symptoms and functional outcome (Kiosses and Alexopoulos, 2005; Kiosses et al., 2001;

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Park et al., 2014; Tam and Lam, 2012). Conversely, three studies reported no effect of depression severity (Mackin and Arean, 2009; Wen et al., 2014) or duration of illness (Gildengers et al., 2012) on either cognitive or functional performance. Park et al. (2014) found that presence of cognitive impairment discriminated between those with or without IADL dysfunction more clearly than presence of MDD. Two studies reported that greater depression severity increased functional impairment (i.e., IADL scores) associated with executive dysfunction (Kiosses and Alexopoulos, 2005; Kiosses et al., 2001).

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ACCEPTED MANUSCRIPT 3.3.1.4 Global Functioning Five studies found an association between cognitive deficits and global dysfunction in mildmoderately depressed patients (Buist-Bouwman et al., 2008; Daniel et al., 2013; Godard et al., 2011; Naismith et al., 2007; Saragoussi et al., 2013). Domains associated with global function include executive function (Daniel et al., 2013; Godard et al., 2011), attention (Cotrena et al., 2016a), memory retention (Naismith et al., 2007), verbal learning (Godard et al., 2011) and self-rated cognitive impairment (McIntyre et al., 2013; Naismith et al., 2007; Saragoussi et al., 2013). Buist

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Bouwman et al. found that self-perceived cognition partially mediated the relationship between a depressive episode and role functioning (Buist-Bouwman et al., 2008). Divergent results were

identified by Caldirola et al. (2014), who found no relationship between cognitive impairment and global function in a study of 117 subjects with DSM-IV mood disorders (Caldirola et al., 2014).

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3.3.1.5 Occupational Functioning

Five of seven studies which measured occupational functioning (i.e., productivity, workplace satisfaction) identified a significant relationship with cognitive performance (Baune et al., 2010; Godard et al., 2011; Kim et al., 2016; McIntyre et al., 2015; Saragoussi et al., 2013). Specifically, executive function (Godard et al., 2011), attention (Godard et al., 2011), verbal memory (Godard et

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al., 2011) and self-rated cognitive deficits were associated with occupational outcomes (Kim et al., 2016; McIntyre et al., 2015; Saragoussi et al., 2013). Depression severity significantly contributed to

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occupational dysfunction in all five studies that measured its effect alongside cognitive performance (Baune et al., 2010; Godard et al., 2011; Gupta et al., 2013; Kim et al., 2016; McIntyre et al., 2015). In

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a large sample of patients, cognitive dysfunction explained greater variance in workplace performance than depressive symptoms (McIntyre et al., 2015). In contrast, a study which examined Treatment Resistant Depression (TRD) patients found that occupational impairment was associated

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with more severe depression, whereas cognitive function was not (Gupta et al., 2013). The null results for cognition in this study may be due to its small sample size (N=33), as well as its sample of

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TRD patients which may differ from other depressed groups (Fava, 2003).

3.3.2 Objective Psychosocial Functioning 3.3.2.1 Social skills Two studies employed the Social Skills Performance Assessment (SSPA); a performance-based test of social competency and communication during a conversation scenario (e.g., greeting a new neighbor) (Gupta et al., 2013; Mueser et al., 2010). Gupta et al. found that poor social performance, was associated with sustained attention, older age, and more severe depression symptoms in a group of thirty three moderately depressed TRD patients (Gupta et al., 2013). Mueser et al. found

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ACCEPTED MANUSCRIPT that verbal fluency most strongly predicted SSPA performance in a group of 40 elderly MDD patients, and 50 Schizophrenia patients.

3.3.2.2 Objective Daily Functioning Gildengers et al. (2012) evaluated daily functioning with the Performance Assessment of Self-Care Skills (PASS). This assessment involves a clinician evaluating the extent to which a patient’s daily tasks (e.g., hygiene) are conducted independently, safely and adequately around the home

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(Gildengers et al., 2012). The results indicated that subjects with impaired executive functioning and information processing were more likely to require assistance and encouragement to complete daily activities (Gildengers et al., 2012) .

3.3.2.3 Employment status

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Baune et al. (2010) reported a strong relationship between unemployment and poor cognition in domains of immediate memory, delayed memory, visuospatial ability, language, and attention, suggesting that cognitive dysfunction across several domains interferes with ability to work in MDD patients. In contrast Withall et al. (2009) found no significant relationship between cognitive performance and employment status. The divergent findings may be caused by the smaller sample

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size in Withall et al. (N = 48) in comparison to Baune et al. (N = 70), which may not have provided

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sufficient power to detect the relationship.

3.3.3 Summary – cross-sectional studies

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In summary, a number of cognitive domains were associated with subjectively assessed QoL, social functioning, global functioning, and occupational functioning. In contrast, only executive functioning and global cognition were associated with subjective daily functioning. A considerably smaller profile

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of cognitive domains was associated with objectively assessed psychosocial functioning. Specifically, social skills were reliant on verbal fluency and attention (Gupta et al., 2013; Mueser et al., 2010),

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and daily functioning reliant on executive functioning and information processing (Gildengers et al., 2012). Divergent results for studies of occupational status restrict conclusions in this domain (Baune et al., 2010; Withall et al., 2009).

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ACCEPTED MANUSCRIPT 3.5 Longitudinal Studies Two longitudinal adult studies investigated the direct relationship between cognitive and functional measures (Jaeger et al., 2006; Withall et al., 2009). Jaeger et al. evaluated functioning with the multidimensional scale of independent functioning (MSIF) (Jaeger et al., 2003), while Withall et al. employed the social and occupational functioning assessment scale (SOFAS) (Goldman et al., 1992). Both studies found that verbal learning, prospective memory and executive function (Jaeger et al., 2006; Withall et al., 2009) predicted functional outcome at 3 (Withall et al., 2009) and 6 months

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(Jaeger et al., 2006).

All three longitudinal elderly studies identified a relationship between cognitive impairment and poor subjective daily functioning (i.e., IADL scores) (Riddle et al., 2015; Wong et al., 2015; Xiang and An, 2015). Wong et al. found that cognitive impairment was associated with poor daily functioning

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(i.e., IADL scores) at 6 months. In a similar vein, the results of Xiang et al., indicated that poorer cognitive functioning predicted deficits in daily functioning over a 12-year period. Xiang et al. also found that patients with both MDD and cognitive dysfunction reported poorer functioning than patients with either MDD or cognitive dysfunction alone (Xiang and An, 2015). Finally, a large study (N=299) of 7 years duration found an association between cognitive impairment, dementia, and

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poor daily functioning (Riddle et al., 2015).

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All longitudinal studies included participants under treatment for MDD, however only one longitudinal study (Withall et al., 2009) reported that both cognition and psychosocial functioning

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significantly improved over time. The five remaining studies reported only improvement in cognitive functioning, or only the linear relationship between cognition and psychosocial functioning (as opposed to the longitudinal relationship between these factors). Characteristics of longitudinal

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studies are presented in Table 3.

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Please insert Table 1 here Please insert Table 2 here Please insert Table 3 here

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ACCEPTED MANUSCRIPT 4. Discussion While a number of methodological limitations were identified, the majority of included studies (22 of 28) reported associations between cognitive deficits and impaired psychosocial outcomes. These relationships were identified in both performance based (n= 4 of 5) and subjective assessments of psychosocial function (n= 17 of 24), with domains of executive functioning, attention, memory, and processing speed primarily associated with functioning. While longitudinal research on this topic is scarce, the available literature points to the importance of executive functioning and attention in

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long-term psychosocial outcomes. Older age and greater MDD symptom severity appear to enhance the cognition-psychosocial functioning relationship, however the role of other illness factors (e.g., dementia, psychosis, illness duration) in this domain remains largely unexplored.

One of the primary goals of the current review was to identify which cognitive domains are

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associated with specific psychosocial issues. The reviewed cross-sectional studies indicated that selfperceived occupational functioning, daily functioning, social relationships, and global functioning are reliant on a broad spectrum of cognitive domains (i.e., executive function, attention, immediate and delayed memory, processing speed, verbal learning, visuospatial memory and language), whereas subjective daily functioning is primary affected by executive functioning and global cognition. Cross-

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sectional studies which employed more objective performance-based measures of functioning confirmed the broad range of cognitive domains implicated in employment, and that daily

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functioning is primarily reliant on executive cognition. In contrast, studies of performance-based social skills found that only verbal fluency and attention performance was predictive of social

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abilities, as opposed to the broad range of domains involved in subjective perception of social and interpersonal functioning. The smaller profile of domains implicated in performance-based social skills may reflect the broader nature of self-perceived social functioning, which likely incorporate

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views of social standing and self-esteem more strongly related to mood state than to objective social ability (Weightman et al., 2014). Taken together, the findings of the reviewed cross-sectional studies

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indicate that deficits in executive functioning, attention, and memory are broadly negatively associated with a number of psychosocial issues.

The second primary goal of this review was to identify which cognitive domains remain predictors of functioning in the long-term, as opposed to only being associated cross-sectionally. The findings of the reviewed longitudinal studies primarily converged with those of cross-sectional studies, with daily, occupational, and social functioning primarily reliant on executive functioning, attention, and memory. Executive and attentional dysfunction may lead to a broad spectrum of functional deficits

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ACCEPTED MANUSCRIPT due to the wide range of daily behaviors reliant on these faculties (e.g., planning future behavior, making decisions, sustaining attention) (Knight and Baune, 2018b; McIntyre et al., 2013; Morris and Jones, 1990). While memory abilities are also crucial, it is noteworthy that the application of memory in everyday life is often integrated with higher order executive abilities (e.g., problem solving, planning) (Baune et al., 2010; Fleming et al., 2004; Morris and Jones, 1990). It follows that the role of memory in long-term functioning is likely a component of executive functioning (Knight et al., 2018). Taken together, the cross-sectional and longitudinal evidence accumulated in this review

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suggests that executive, attentional, and memory deficits are associated with longitudinal daily, occupational and social impairment in MDD. It is possible that cognitive domains implicated in crosssectional (but not longitudinal) studies (e.g., processing speed, language) are more likely to be

tangentially associated with psychosocial outcomes by mutual associations with other symptoms of

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MDD (e.g., impaired mood).

Two important questions raised by the included longitudinal research are (1) whether observed psychosocial functioning can improve detection of cognitive impairment, and (2) whether cognitive dysfunction will lead to psychosocial deficits. Findings in the reviewed studies provide a broad answer to (1), with one study found that poor daily functioning was associated with higher rates of

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cognitive decline (Riddle et al., 2015), while other studies indicated that patients with daily, occupational, or social deficits appear more likely to suffer cognitive deficits in executive, attention,

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and memory. Reaching consensus on (2) is reliant on the findings of highly controlled longitudinal research, however currently available longitudinal research is heterogenous with regards to patient

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characteristics (e.g., age), management of treatment and methodological control for comorbidity (e.g., dementia, psychosis). As a result, consensus on the extent to which cognitive deficits lead to

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psychosocial dysfunction in the long-term remains elusive.

4.1 Influence of clinical and demographic factors on the relationship

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It is important to consider which patient characteristics influence the cognition-functioning relationship in MDD, as certain patient groups may be more or less vulnerable to cognitive and psychosocial dysfunction. Four of the currently reviewed studies found that greater depression severity enhances the negative effect of cognitive deficits on psychosocial dysfunction (Kiosses and Alexopoulos, 2005; Kiosses et al., 2001; Park et al., 2014; Tam and Lam, 2012). In addition, it was found that psychosocial dysfunction was greater in those with cognitive deficits and MDD in comparison to those with either cognitive dysfunction or MDD alone (Xiang and An, 2015). These findings imply that cognitive dysfunction mutually interacts with other symptoms of MDD

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ACCEPTED MANUSCRIPT (Weightman et al., 2014), exacerbating the negative relationship between cognitive deficits and psychosocial functioning.

Age also played an important role in the cognition-functioning relationship, with the reviewed studies typically finding that older age was associated with greater cognitive deficits and poorer psychosocial functioning (Cotrena et al., 2016a; Daniel et al., 2013; Gildengers et al., 2012; Gupta et al., 2013; Kiosses et al., 2001; Mackin and Arean, 2009; Riddle et al., 2015). The negative effect of

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age may be caused in part by the contribution normal age-related cognitive decline, which may compound that associated with MDD, and increase susceptibility to psychosocial dysfunction.

Consequently, late onset depression likely presents a differing form of depression in which the

pathology of cognitive and psychosocial deficits is more multifaceted than in younger adults, in

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whom environmental and genetic factors may play a greater role (Laks and Engelhardt, 2010).

The role of dementia should also be considered, as this illness contributes independently to psychosocial dysfunction, and may compound cognitive deficits associated with MDD (Spitznagel et al., 2006). Accordingly, it is crucial for authors to clarify whether their findings exclude dementia patients, or clearly partition those findings which relate to dementia patients. In the present review,

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two studies stratified participants by “cognitively impaired / cognitive intact” without reporting dementia status (Park et al., 2014; Xiang and An, 2015). As a result, it is not possible to discern the

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role of “cognitive impairment” in these studies from other factors associated with dementia. The remaining nine elderly studies excluded dementia patients and reported associations between

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cognitive and psychosocial functioning, with several reporting poorest psychosocial outcomes in those with cognitive impairment in conjunction with MDD. These findings support the notion that

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cognitive dysfunction contributes to psychosocial deficits in elderly MDD patients without dementia.

Previous reviews suggest that psychotic symptoms also contribute to cognitive and psychosocial

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deficits in mood disorders (Bora et al., 2009; Fleming et al., 2004), highlighting the need to account of psychotic features in MDD patients. In the present review, the slim majority of studies (n= 15) accounted for psychotic features either by excluding patients with psychotic features, statistically adjusting for psychotic symptoms, or partitioning analyses by presence of psychotic illness (e.g., psychotic Bipolar / MDD) (Gildengers et al., 2012; Mueser et al., 2010). Presence of psychotic symptoms within MDD populations ranged from 6-20% of study participants, suggesting that those studies which did not account for psychosis (n= 14) may include a significant number of patients with psychotic features. It is not possible to discern the contribution of psychosis to psychosocial

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ACCEPTED MANUSCRIPT functioning in these studies. In addition, no studies specifically examined whether the presence of psychosis influenced the relationship between cognitive and psychosocial functioning in MDD, pointing to the need for greater acknowledgment of psychoses in future research.

In summary, it is apparent that older age and greater MDD symptom severity were reliably associated with increased cognitive (i.e., executive functioning, self-perceived cognition) and psychosocial impairment (i.e., global and daily functioning), and may enhance the relationship

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between these factors (Xiang and An, 2015). Consequently, cognitive and psychosocial assessments are warranted in older, and more severely depressed patients who may be more vulnerable to

cognitive and psychosocial dysfunction. Presence of dementia or psychotic symptoms may also enhance cognitive and psychosocial issues. However, the methodological limitations and paucity of

4.2 Methodological limitations of literature

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studies do not enable firm conclusions in these domains.

Heterogeneity in assessments tools, and the use of non-standardized assessments in the presently reviewed studies makes direct comparisons between studies difficult, particularly with regards to isolating functional relationships with specific cognitive domains. This difficulty highlights the need

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for reliable, valid and widely supported measures of cognition (e.g., the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS)) and psychosocial functioning (e.g., ADLs, FAST,

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SSPA). In addition, patient samples were heterogeneous, often comprised of both inpatients and outpatients, patients with or without psychotic symptoms and both remitted and currently

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depressed individuals. Additionally, studies on elderly cohorts varied in their cut off for age, ranging from 50 through to 70 years. Further research is needed to determine whether the findings of this

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review are consistent across these patient groups (Knight et al., 2018; Knight and Baune, 2018b).

Only four adult studies and two elderly studies were longitudinal, and none incorporated

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performance-based measures of functioning, relying on subjective functional measurements (e.g., self-reports, clinician interviews). The lack of performance-based measures (e.g., PASS, SSPA) represents a key limitation of the current longitudinal literature, as the results are more vulnerable to patient bias and variation in clinician judgements. An additional limitation in longitudinal elderly literature was the use of cognitive assessments which relied on composite scores of overall cognitive functioning (e.g., the health retirement study (HRS) cognition test) (Xiang and An, 2015), as opposed to using tests which differentiate between specific cognitive domains (e.g., executive functioning, attention). Assessments of overall cognition lack the specificity to identify domain-specific

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ACCEPTED MANUSCRIPT relationships, and hence did not enable detection of which cognitive domains are more crucial treatment targets in elderly MDD.

The methodological limitations and strengths identified present a valuable opportunity for future investigators to pursue new avenues in this domain. In particular, there is a great need for longitudinal studies of cognitive and psychosocial dysfunction, which report both the relationship between these factors and the significance of changes between baseline and follow-up. Such work

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would be strengthened by inclusion of domain-specific measures of cognition designed for use in MDD (e.g., the SCIP-D, THINC-it tool), as well as objective measures of psychosocial functioning (e.g., the SSPA); both of which are hitherto absent from longitudinal research. Both longitudinal and cross-sectional studies are needed which discern differences in the cognition-psychosocial

functioning relationship between different patient cohorts (e.g., with/without psychotic features),

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relative to healthy controls. Studies comparing specific cohorts should adjust or partition analyses by factors which could influence the cognition-psychosocial functioning relationship (e.g., age, dementia, MDD onset interval, MDD severity). Such research may discern which factors enhance the relationship between cognition and psychosocial functioning in MDD.

M

4.4 Extensions to Evans’ et al. (2014) findings

A previous review of this topic by Evans et al. (2014), reported that cognitive function is broadly

ED

associated with psychosocial impairments in MDD and noted the weak quality of evidence available at the time. The findings of the current review extend our knowledge of this sector by examining 9

PT

adult, and 11 elderly studies which were not included in Evans’ et al. Key findings in the elderly studies included association between cognitive deficits (i.e., executive, processing speed) and psychosocial dysfunction (i.e., global, daily, and social functioning), with several studies reporting

CE

that this relationship occurred independently of MDD symptom severity. Newly reported adult studies identified relationships between cognition and global psychosocial functioning, QoL, and

AC

occupational functioning; of which executive functioning, global cognition, and self-perceived cognitive function were primarily associated. The additional adult studies also reinforce the conclusion that greater depression severity is associated with greater cognitive and psychosocial impairment, and may enhance the negative relationship between cognition and functioning. However, these studies suffered several of the methodological drawbacks identified by Evans, including heterogeneous samples (e.g., inclusion of patients with psychosis), small sample sizes, lack of prospective designs, and lack of validated assessments for use in MDD (e.g., Screen for Cognitive

16

ACCEPTED MANUSCRIPT Impairment in Depression (SCIP-D), THINC-it Tool), further underscoring the need for deployment of more appropriate assessment tools in this domain of research.

4.4 Conclusions and implications The principal implications of this review are (1) that executive functioning, attention, and memory are the cognitive domains most closely associated with functional issues in MDD, (2) cognitive deficits are associated with short-term and longitudinal functional deficits. Finally, (3) older age and

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greater illness severity appear to increase susceptibility to and magnitude of psychosocial deficits in MDD. The roles of psychosis, dementia, illness duration, and other psychiatric and medical

comorbidities in the cognition-functioning relationship in MDD are largely unexamined and present valuable avenues for future research. Such research will be improved by the development of goldstandard cognitive and functional measurements for MDD, as has been done for Schizophrenia (Lam

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et al., 2014).

Acknowledgement Financial support and sponsorship

The study was supported by an unrestricted grant of the James and Diana Ramsay Foundation,

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Adelaide, Australia. The funding body had no impact on the design or the content of the presented

Conflict of interest

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work.

PT

B.T.B. received speaker/consultation fees from: AstraZeneca, Lundbeck, Pfizer, Takeda, Servier,

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Bristol Myers Squibb, Otsuka, and Janssen-Cilag. O.C, M.K and N.M declare no conflicts of interest.

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ACCEPTED MANUSCRIPT References

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Table 1. Sample Characteristics, Assessments and Findings for Included Studies in Adults (N=17)

McCall & Dunn 2003 (United States)

Cognitive deficits are associated with functional impairment in severely depressed patients

Jaeger et al. 2006 (United States)

Neurocognitive deficits and disability in major depressive disorder

Yes

Naismith et al. 2007 (Australia)

Disability in major depression related to selfrated and objectivelymeasured cognitive deficits: a preliminary study

Yes

Buist-Bouwman et al. 2008 (Netherlands)

Mediators of the association between depression and role functioning

Withall Harris & Cumming 2009

The relationship between cognitive function and

No

CE

AC

Sample Size, (Mean Age) N= 77 MDD inpatients (57.3)

Diagnostic Tool

Depression Severity Mean

Cognitive Measures

Assessments of Functioning

Results

SCID/DSM-IV criteria

HAM-D 28.9 BDI 34.3

MMSE RAVLT RFLT

Poorer global cognition is associated with poorer IADL functioning in severely depressed patients. IADL scores were more closely related to MMSE scores than other measures of cognitive function. Each dimension of QoL had a unique relationship with age, mood and cognition.

Longitudina l

N= 48 MDD inpatients (39.6)

SCID/DSM-IV criteria

HAM-D 16.47

WAIS-R Concentration ET (D2) WCST COWA Wechsler Memory Scale RFFT

Daily Living and Role Functioning (DLRF) and Relation to Self and Others (RSO) Activities of Daily Living (ADL) and Instrumental Activities of Daily Living (IADL) Scales Personal Self-Maintenance Scale (PSMS) Multidimensional Scale of Independent Functioning (MSIF)

CrossSectional

N=21 MDD outpatients (53.9) N= 21 Age, Sex and Education Matched Healthy Controls N = 847 MDD outpatients (Mean age not reported)

DSM-IV criteria

HAM-D 21.7

NART TMT-A & TMT-B WMS-R RAVLT Stroop Test TOL

Brief Disability Questionnaire (BDQ) 12 Item Short-Form Health Survey (SF-12)

Depression severity is a strong predictor of functional disability whereas physical disability is strongly predicted by self-rated overall cognitive dysfunction.

CIDI/DSM-IV criteria

HAM-D 16.47

WHO-DAS

WHO Disability Assessment Schedule (WHO-DAS)

Approximately half of the impact of MDE on role functioning was mediated by problems with Cognition and by feelings of embarrassment.

N= 48 MDD inpatients

DSM-IV criteria

HAM-D At Initial

NART Donders

Social and Occupational Functioning Assessment

Cognitive variables (especially those that reflect executive function) measured at

CrossSectional

AN US

Study Design

M

Included in Evans et al. (2014)? Yes

ED

Title

PT

Author, Year

Yes

CrossSectional

Longitudina l

Nearly 60% of the sample remained significantly disabled at follow up suggesting high rates of persisting functional disability in MDD patients. NC deficits play an important role in functional recovery. Selected cognitive domains (visuo-spatial functions, learning and motor measures) tested at baseline were predictive of functionality at 6 months.

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(37.9)

The role of cognitive impairment in general functioning in major depression

Yes

CrossSectional

Godard et al. 2012 (Canada)

Psychosocial and neurocognitive profiles in depressed patients with major depressive disorder and bipolar disorder

Yes

CrossSectional

Shimizu et al. 2013 (Japan)

Neurocognitive impairments and quality of life in unemployed patients with remitted major depressive disorder

Yes

AC

CE

PT

CrossSectional

Computerized Simple RT Task WMS-R CVLT PMT Stroop Test WCST COWAT MSET RBANS

Scale (SOFAS) Employment Status

admission were valid predictors of functional outcome approximately 4 months later.

Medical Outcomes Study Short Form Health Survey (MOS-SF-36) Activities of Daily Living (ADL) and Instrumental Activities of Daily Living (IADL) Scales Employment status

Cognitive function was not related to physical or mental QoL or impairments in ADL/IADL. A relationship between unemployment and poor cognitive function across all domains was found.

N=70 MDD outpatients Current MDD = 26 (46.0) Previous MDD = 44 (44.2) N= 206 Age and Gender Matched Healthy Controls N=16 MDD outpatients (49.5) N= 30 Age and Education Matched Controls

Mini International Neuropsychiatric Interview (MINI)

HAM-D Current MDD= 18.0 Previous MDD= 6.8

Mini International Neuropsychiatric Interview (MINI)

HAM-D 31.2 MADRS 28.5

CPT D-KEFS CogitEx II CVLT WASI

Longitudinal Interval Follow-up Evaluation-Range of Impaired Functioning Tool (LIFE-RIFT)

During an episode, MDD and BD patients had global psychosocial dysfunction. Severity of depression and cognitive function were significantly associated with psychosocial functioning.

N= 43 Remitted MDD outpatients (38.3) N= 43 Age and Education Matched Healthy Controls

Mini International Neuropsychiatric Interview (MINI)

HAM-D 2.9

WCST CPT TMT-A & TMT-B Verbal Fluency Test AVLT

Medical Outcomes Study Short Form Health Survey (MOS-SF-36)

Residual depressive symptoms were strongly associated with QoL. Remitted MDD patients had poorer cognitive performance compared to controls in domains of psychomotor speed, attention, & verbal memory.

AN US

Baune et al. 2010 (Australia)

Assessment= 38.3 At 3 Months post discharge= 10.7

M

clinical and functional outcomes in major depressive disorder

ED

(Australia)

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Relationships among neurocognition, symptoms, and functioning in treatment-resistant depression

Yes

CrossSectional

N=33 TRD outpatients (45.8)

SCID/DSM-IV

MADRS 25.06

Saragoussi et al. 2013 (Europe)

Patient-reported cognitive dysfunction negatively impacts functioning in patients with major depressive disorder – Preliminary findings from the PERFORM study

No

Longitudina l

N= 947 MDD outpatients (Mean age not reported)

DSM-IV criteria

Not Reported

Daniel et al. 2013 (Italy)

Cognitive impairment and its associations with the path of illness in affective disorders: A comparison between patients with bipolar and unipolar depression in remission

No

CrossSectional

DSM-IV criteria

HAM-D 3.24

BSRT WCST TMT-B Stroop Test SNAT Digit Span

Caldirola et al. 2014 (Italy)

Self-reported quality of life and clinician-related functioning in mood and anxiety disorders: Relationships and neuropsychological correlates The impact of cognitive impairment on perceived workforce performance: Results from the international mood disorders collaborative project

No

CrossSectional

N= 25 MDD outpatients (50.6) N= 29 Healthy Age, Gender and Education Matched Controls N= 39 MDD inpatients (57.6)

DSM-IV criteria

Not Reported

N= 260 MDD inpatients and outpatients (41.0)

Mini International Neuropsychiatric Interview (MINI)

Not Reported

NSRT Attentional Matrices ROCF Verbal Fluency Tests Token test ASRS – IS

AC

M

ED CrossSectional

PT

No

CE

McIntyre et al. 2015 (Canada)

CPT-IP HVLT LNST TSCT TMT-A & TMT-B COWAT Animal Naming Test Stroop test PDQ-5

AN US

Gupta et al. 2013 (Canada)

Social Skills Performance Assessment (SSPA) Advanced Finances Task (AFT) Longitudinal Interval Follow-up Evaluation-Range of Impaired Functioning Tool (LIFE RIFT)

Impairment in all 4 of the functional domains was associated with more severe depressive symptoms. Cognitive and depressive symptoms together are associated with functional competence but depressive symptoms alone are more strongly related to functional performance.

Sheehan Disability Scale (SDS) Work Productivity and Activity Impairment Questionnaire (WPAI) EuroQoL-5 Dimensions (EQ5D) 12 Item Short-Form Health Survey (SF-12) Global Assessment of Functioning (GAF)

Patient reported cognitive deficit was associated with impairment of overall functioning, QoL and productivity (In addition to any negative impact of severity of depression).

World Health Organization Quality of Life AssessmentBrief Form (WHOQOL-BREF) Global Assessment of Functioning Scale (GAF)

No significant relationship was found between individual perception of QoL and clinician rated psychosocial functioning or between cognitive impairment and lower QoL/clinician related functioning.

Sheehan Disability Scale (SDS) Endicott Work Productivity Scale (EWPS) Quality of Life Enjoyment Questionnaire (Q-LES-Q)

A modest correlation exists between severity of depression and global disability or work productivity/performance, as well as between cognitive function (attention) and global disability or work productivity/performance.

Global functioning was moderately associated with executive function performance even when controlling for sociodemographic and clinical variables. Impairment in executive function may partly contribute to impairments in psychosocial functioning in euthymic patients with mood disorders.

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Quality of life, functioning and cognition in bipolar disorder and major depression: A latent profile analysis

No

CrossSectional

N= 29 MDD outpatients (Mean age not reported) N= 64 Age and Education Matched Healthy controls

DSM-V criteria

HAM-D Cluster 1 2.08 Cluster 2 6.68 Cluster 3 14.10 Cluster 4 20.26

Kim et al. 2016 (South Korea)

A cross-sectional study of functional disabilities and perceived cognitive dysfunction in patients with major depressive disorder in Korea: The PERFORM-K study

No

CrossSectional

N= 312 MDD outpatients (45.2)

Mini International Neuropsychiatric Interview (MINI)

MADRS 28.9

Cotrena et al. 2016 (Brazil)

Executive Function impairments in depression and bipolar disorder: Association with functional impairment and quality of life

No

CrossSectional

N= 45 MDD outpatients (32.5) N= 89 Age, Sex and Education Matched Healthy Controls

DSM-V criteria

HAM-D 8.77

Kamenov et al. 2016 (Asia, Africa, Europe & Latin America)

Which are the most burdensome functioning areas in depression? A cross-national study

N= 4051 MDD outpatients (60.0)

CIDI/DSM-IV

Not Reported

M

ED PT

AC

CE

No

CrossSectional

MMSE WAIS III IGT MDMQ HSCT TMT-A & TMT-B Verbal Fluency tasks WCST Sentence-Word Span Digit Span DAT & SAT Stroop Test PDQ-D

WHO Disability Assessment Schedule (WHO-DAS)

When placed on a continuum of better QoL and functioning, better cognitive performance and milder depressive symptoms to the opposite of this, the functional impairments in the more severe groups are more associated with cognitive performance than depression itself compared to the less severe groups where functional impairments were more correlated to the depression than cognitive impairments.

Sheehan Disability Scale (SDS) The Work Productivity and Activity Impairment Questionnaire (WPAI) EuroQOL Five Dimensions Questionnaire (EQ-5D)

MMSE WAIS III IGT MDMQ HSCT TMT-A & TMT-B Verbal Fluency Tasks WCST Sentence-Word Span Digit Span DAT & SAT Stroop Test A previously developed multidomain measure (Included mobility, self-care, cognition, pain, interpersonal activities, domestic life and work, sleep

WHO Disability Assessment Schedule (WHO-DAS)

Grater functional disability, greater impairment in daily activities and worse quality of life were associated with more severe depression and worse perceived cognitive dysfunction. Employed patients who reported more severe cognitive dysfunction also reported worse work related-productivity outcomes, irrespective of depression severity. The association between cognitive performance, self-reported disability and quality of life is strongest in patients with BD-I compared to patients with BD-II or MDD. The effect of depressive symptoms on cognition and psychosocial functioning is not mood state dependent.

AN US

Cotrena et al. 2015 (Brazil)

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WHO Quality of Life Instrument (WHOQOL)

The functioning domains most associated with QoL were domestic life and work and interpersonal activities. Sleep and energy, mobility, and cognition were also significantly related to QoL but effect sizes were smaller.

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and energy and affect.)

AC

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Key: MDD= Major depressive disorder, MDE= Major depressive episode, BD= Bipolar disorder, TRD= Treatment resistant depression, HAM-D= Hamilton depression rating scale, BDI= Beck depression inventory, MADRS= Montgomery-Asberg depression rating scale, DSM= Diagnostic and statistical manual of mental disorders, SCID= structured clinical interview for DSM-V, CIDI= Composite international diagnostic interview, MMSE= Mini Mental State Exam, DRS= Dementia Rating Scale, WHO DS= WHO Disability Assessment Scale, SAT= Sustained Attention Test, DAT= Divided Attention Test IGT= Iowa Gambling Task, MDMQ= Melbourne Decision Making Questionnaire, HSCT= Hayling Sentence Completion Test, TMT= Trail Making Test, WCST= Wisconsin Card Sorting Test, PDQ= Perceived Deficits Questionnaire, ASRS= Adult ADHD Self Report Scale, ROCF= Rey-Osterrieth Complex Figure Copy Test, NVSRT= Novelli’s Story Recall Test, SNAT= Symbol Number Association Test, TOL= Tower of London, BSRT= Babcock Story Recall Test, RFLT= Rey Figure Learning Test, NART= National Adult Reading Test, CVLT= California Verbal Learning Test, PMT= Prospective Memory Task, MSET= Modified Six Element Test, RBANS= Repeatable Battery for the Assessment of Neuropsychological Status, CPT= Continuous Performance Test, CPT-IP= Continuous Performance Test-Identical Pairs Version, D-KEFS= Delis-Kaplan Executive Function System, AVLT= Auditory Verbal Learning Test, LNST= Letter Number Sequencing Test, TSCT= The Symbol Coding Task, NSRT= Novelli’s Story Recall Test, RFFT= Ruff Figural Fluency Test

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Table 2. Sample Characteristics, Assessments and Findings for Included Studies in the Elderly (N=11)

Executive dysfunction and disability in elderly patients with major depression

Kiosses & Alexopoulos 2005 (United States)

IADL functions, cognitive deficits, and severity of depression

No

CrossSection al

Mackin & Arean 2009 (United States)

Impaired financial capacity in late life depression is associated with cognitive performance on measures of executive functioning and attention

No

CrossSection al

Mueser et al. 2010 (United States)

Neurocognition and social skill in older persons with schizophrenia and major mood disorders: an analysis of gender and diagnosis effects

No

CrossSection al

Lam & Tam 2012 (China)

Cognitive function, functional performance and severity of depression in Chinese older persons with lateonset depression

AC

CrossSection al

No

Diagno stic Tool

Depression Severity Mean

Cognitive Measures

Assessments of Functioning

Results

RDC and DSM-IV criteria

HAM-D 27.29

DRS

Multilevel Assessment Instrument (MAI-IADL)

DSM-IV criteria

HAM-D 12.84

MMSE DRS

Multilevel Assessment Instrument (MAI-IADL)

DSM-IV criteria

Not Reported

BVMT-R HVLT-R MVPT-3 SDMT-O TMT-A & TMT-B BNT COWAT WCST-64 Stroop Test WAIS Digit Span, Similarities, LNS Delis-Kaplan Executive Functioning system (DKEFS)

Independent Living Scales Managing Money Scale (ILS MM)

Abnormal initiation/preservation (a reflection of executive function) is the cognitive impairment most likely to contribute to disability in elderly adults with major depression when compared to attention, construction, conceptualization and memory. Abnormal scores in initiation/preservation alone or interacting with depression severity were associated with impairment in most IADL’s. Depression severity and impairment in specific cognitive domains alone or in the presence of depression are associated with impairment in seven out of eight IADL functions. Individuals with LLD had a significantly higher rate of impaired financial capacity compared to the comparison group. Performance on measures of executive function and attention but not depression severity was strongly associated with financial capacity performance in LLD.

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Kiosses et al. 2001 (United States)

Sample Size, (Mean Age) N= 126 Elderly Patients with MDD (70.5) N=105 NonDemented Depressed Elderly Patients (78.4) N= 65 LLD Patients (70.1) N= 32 Controls

N= 183 Patients with Severe Mental Illness

CrossSection al

N= 105 Elderly LO MDD Patients (74)

AN US

Study Design

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Included in Evans et al. (2014)? No

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Title

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Author, Year

DSM-IV criteria

BPRS – Depression Subscale MDD group 2.66

DSM-IV criteria

HAM-D 18

CMMSE ADAS-Cog VFT Digit Span and Visual Span TMT

Social Skills Performance Assessment (SSPA) Social Network Questionnaire Quality of Life Interview Disability Assessment for Dementia Scale (DAD)

Social contact and cognitive functioning were strongly associated with social skills in people with schizophrenia and schizoaffective disorder but not those with mood disorder.

Severity of depression, presence of apathy, mild Parkinson disease signs and executive function were independent predictors for functional performance in depressed elderly subjects.

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Cognition in older adults with bipolar disorder versus major depressive disorder

No

CrossSection al

N= 122 MDD (74.3) N= 92 Controls

DSM-IV criteria

HAM-D-17 6.0

Wen, Hebscher & Lee 2014 (Canada)

Instrumental activities of daily living in remitted late-life depression: a preliminary study

No

CrossSection al

DSM-IV criteria

HAM-D IADL intact group 7.24 IADL impaired group 7.92

Park et al. 2014 (Korea)

Cognitive impairment and depression in the early 60’s: Which is more problematic in terms of instrumental activities of daily living?

No

CrossSection al

Riddle et al. 2015 (United States)

Disability but not social support predicts cognitive deterioration in late-life depression

No

Longitu dinal

N= 30 NonDemented Elderly Patients with rLLD (67) N= 785 MDD outpatient s (62.4) N= 2249 Nondepressed N= 299 Depressed Older Adults (69.8)

Wong et al. 2015 (China)

Six-month follow-up of cognitive impairment and depressive

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Longitu dinal

N= 52 LOD Patients (73.7)

Performance Assessment of Self-Care Skills (PASS)

Clinical Dementia Rating (CDR) Scale

The impaired-IADL group performed significantly worse on the digit span test and the TVLT than the intact-IADL group. Remitted LLD patients with different levels of IADL had different severity of apathy and cognitive impairments.

MDD patients GDS-15 >8

Korean MMSE

Lawton’s Independent Activities of Daily Living Scale (L-IADL)

Compared with depression, cognitive impairment was more strongly associated with IADL impairment. The presence of cognitive impairment was a better discriminator between participants with and without IADL impairment than the presence of depression.

MADRS NC 22 CIND 25 Dementia 28.7

CERAD battery

Basic Activities of Daily Living (BADL) and Independent Activities of Daily Living (IADL) Scales

Increased IADL deficits predicted subsequent conversion to a cognitive diagnosis in depressed older adults, but BADL deficits and social support did not predict a cognitive decline. IADL deficits precede cognitive impairment in late-life depression, and this is independent of depression severity and age.

HAM-D At Baseline 12.3

HKMCA

Instrumental Activities of Daily Living

Those who were cognitively impaired had a lower IADL score than the normal (not cognitively impaired) group. Those with greater baseline functional

M

GDS score above 8

ED

PT

CE

No

WMS II CVLT WCST TMT-A, TMT-B Stroop Test Executive interview VFT DSST Spot the Word LFT Silly Sentences ROCF SDT FTT Block Design GPT Digit Span BNT Clock Test Digit Span DSST 3-Dimensions Block Construction Test BVRT TVLT

AN US

Gildengers et al. 2012 (United States)

NIMH diagnos tic intervie w schedul e and DSM-IV criteria ICD-10 criteria

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The domains of Information processing speed and executive function were the most impaired for both MDD and BD subjects. Cognitive function was highly related to performance of C-IADL’s. Worse cognitive performance was related to increased assistance required in task completion. C-IADL’s were significantly correlated with all measures of cognition.

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Xiang & Ruopeng 2015 (United States)

The impact of cognitive impairment and comorbid depression on disability, health care utilization, and costs

At 6 Months 5.6

No

CrossSection al

N= 18,315 Adults >51 (65.3)

CES-D score above 3

MDD patients CES-D >3

(IADL) Scale

Telephone Interview for Cognitive Status (10 item immediate and DRT, serial 7’s subtraction test, backward-counting)

Activities of Daily Living (ADL) and Instrumental Activities of Daily Living (IADL) Scales

AN US

symptoms in late-onset depression

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impairment had more persistent cognitive impairment at 6 months. Functional impairment at baseline is a marker for persistent cognitive impairment When treating depressed patients that are cognitively impaired, depressed symptoms improve in a shorter time than the cognitive impairment does. Cognitive impairment and depression independently predicted functional limitations as well as hospital and nursing home admissions and out of pocket expenditures. Cognitive impairment plus comorbid depression increased the odds of ADLs three-fourfold.

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Key: MDD= Major depressive disorder, BD= Bipolar Depression, LLD= Late life depression, LOD= Late onset depression, LOMDD= Late onset major depression, MCI= Mild cognitive impairment, CIND= Cognitive impairment not dementia, DSM= Diagnostic and statistical manual of mental disorders, ICD-10= International statistical classification of diseases and related health problems 10th revision, RDC= Research diagnostic criteria, BPRS= Brief psychiatric rating scale, HAM-D= Hamilton depression rating scale, GDS= Geriatric depression scale, MADRS= Montgomery-Asberg depression rating scale, NIMH= National institute of mental health, CES-D= Centre for epidemiologic studies depression scale, D-KEFS= Delis-Kaplan Executive Function System , COWAT= Controlled Oral Word Association Test, BNT= Boston Naming Test, SDMT-O= Symbol Digit Modality Test – Oral Version, BVMT-R= Brief Visuospatial Memory Test-Revised, HVLT-R= Hopkins Verbal Learning Test-Revised, MVPT-3= Motor Free Visual Perception Test-Third Edition , LFT= Letter Fluency Test, SDT= Simple Drawings Test, VFT= Verbal Fluency Test, FTT= Finger Tapping Test, GPT= Grooved Pegboard Test, DSST= Digit Symbol Substitution, BVRT= Benton Visual Retention Test, TVLT= Taiwanese Verbal Learning Test, CERAD= Consortium to Establish a Registry for Alzheimer’s Disease Battery, HKMCA= Hong Kong Montreal Cognitive Assessment, DRT= Delayed Recall Te

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Table 3. Longitudinal study characteristics in Adult (n=2) and Elderly (n=3) studies Title

Xiang & Ruopeng 2015 (United States)

The impact of cognitive impairment and comorbid depression on disability, health care utilization, and costs Disability but not social support predicts cognitive deterioration in late-life depression

Jaeger et al. 2006 (United States)

Management of MDD treatment

Onset of MDE in relation to baseline

Change over time (baseline – follow-up) in cognition and/or psychosocial functioning

Treatment of MDD was not considered in analyses. However, the authors used out of pocket expenses as an outcome, in which may be included paid treatments for MDD

Participants were currently depressed at baseline. MDD onset not reported

Only linear relationships between baseline and follow-up were examined, no cognition or psychosocial changes over time was reported. Factors associated with poor functional outcomes were cognitive dysfunction, greater MDD symptom severity, and older age.

Cognition (BL+FU): CERAD battery Psychosocial (BL+FU): BADL, IADL

All participants were receiving antidepressants. Analyses adjusted for symptom severity at baseline (i.e., MADRS score)

Participants were currently depressed at baseline. MDE onset not reported

All participants received treatment over the 6month study period. Type of treatment is not specified

All participants had illness onset at ≥ 50years of age. Mean age of participants was 73.7. Mean years since first hospitalization for MDD was 6.9 (SD= 10. 3).

Changes in psychosocial functioning over time between baseline and follow-up were reported separately for “normal”, cognitively impaired, and dementia groups. However inferential tests of the baseline – follow-up differences are not provided. Of 28 participants with cognitive impairment at BL, 8 returned to “normal” cognitive functioning at FU. Change in cognitive function between BL and FU was significant (p< .05).

Six-month followup of cognitive impairment and depressive symptoms in lateonset depression Neurocognitive deficits and disability in major depressive disorder

Elderly

Time between baseline and follow-up was 6 months

Cognition (BL+FU): HKMCA Psychosocial (BL): IADL

Adult

Time between baseline and follow-up was 6 months

Cognition (BL+FU): WAIS-R Concentration ET (D2), WCST, COWA, Wechsler Memory Scale RFFT Psychosocial (FU): MSIF

The relationship between cognitive function and clinical and functional outcomes in major depressive disorder

Adult

Time between baseline and follow-up was 3 months

Participant who planned on receiving ECT. The majority (62.6%) of participants were taking anti-depressant. Use of additional medications (e.g., sedatives) were also recorded; mean number of medications at baseline was 2.69 (SD= 1.35)

Attention, executive function, verbal fluency and language improved at FU relative to BL. Working memory, visuospatial functioning, learning, and motor functions did not show significant change over time.

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Participant who had received or planned Participants were Executive functioning and global psychosocial to receive ECT were excluded, as were currently depressed functioning were significantly improved at FU participants taking tricyclic at baseline. MDD relative to BL (ps <.001). Fewer participants antidepressants. Other treatments were onset not reported were unemployed at FU (27%) relative to permitted. Of 48 participants, 43 baseline (29%), however the statistical maintained the same treatment over the significance of employment status change was 3 month study period, the remaining 5 not reported participants had discontinues treatment Key: BL= baseline, FU= Follow-up, MSIF= Multidimensional Scale of Independent Functioning, SOFAS= Social and Occupational Functioning Assessment Scale, ECT= electro convulsive-therapy were excluded, CERAD= Consortium to Establish a Registry for Alzheimer’s Disease Battery, ALD= Activities of Daily Living, IADL= Instrumental Activities of Daily Living Scales, BADL= Basic Activities of Daily Living, HKMCA= Hong Kong Montreal Cognitive Assessment, WAIS-R Wechsler Adult Intelligence Scale Revised, WCST= Wisconsin Card Sorting Test, COWAT= Controlled Oral Word Association Test, , RFFT= Ruff Figural Fluency Test, NART= National Adult Reading Test, RT= reaction time, WMS-R= Wechsler Memory Scale Revised, PMT= Prospective Memory Task, MSET= Modified Six Element Test, RBANS

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CE

Withall Harris & Cumming 2009 (Australia)

Baseline cognitive and psychosocial assessment were performed between 1998 and 2010. Mean time between baseline and follow-up assessment was 9.3 years Baseline Data collected over 7 years. Time between baseline and follow-up was 1 year

Inclusions at baseline (BL) and Follow-up (FU) assessment Cognition (BL+FU): Telephone Interview for Cognitive Status Psychosocial (BL+FU): ADLs, IADLs

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Wong et al. 2015 (China)

Elderly

Timing of assessments

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Riddle et al. 2015 (United States)

Elderly / Adult Study Elderly

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Author, Year

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Cognition (BL+FU): NART Donders Computerized Simple RT Task, WMS-R, CVLT, PMT, Stroop Test, WCST, COWAT, MSET Psychosocial (BL+FU): SOFAS Employment Status

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