Vascular risk factors for depression and apathy Lonneke Wouts

Vascular risk factors for depression and apathy Lonneke Wouts

Photography, design and lay-out Paulien Varkevisser | fotografie & vormgeving, Nijmegen www.paulienvarkevisser.com Printing Ipskamp Printing B.V., Enschede, the Netherlands © 2023, Lonneke Wouts No part of this thesis may be reproduced, stored in a retrieval system of any nature, or transmitted in any form or by any means without prior written permission of the author, or when appropriate, the holder of the copyright.

Vascular risk factors for depression and apathy Proefschrift ter verkrijging van de graad van doctor aan de Rijksuniversiteit Groningen op gezag van de rector magnificus prof. dr. C. Wijmenga en volgens besluit van het College voor Promoties. De openbare verdediging zal plaatsvinden op donderdag 20 april 2023 om 12.45 uur door Lonneke Wouts geboren op 24 juni 1977 te Tilburg

Promotores Prof. dr. R.C. Oude Voshaar Prof. dr. A.T.F. Beekman Copromotor Dr. R.M. Marijnissen Beoordelingscommissie Prof. dr. R.A. Schoevers Prof. dr. B.C. van Munster Prof. dr. F. Verhey

Beeld: Helma Wouts-Meeuwissen, keramiek

Table of contents TABLE OF CONTENTS

Chapter 1 Introduction Part I Chapter 2 Cardiac disease, depressive symptoms, and incident stroke in an Elderly Population Chapter 3 Depression in context of low neuroticism is a risk factor for stroke: a 9-year cohort study Chapter 4 The interaction between cerebrovascular disease and neuroticism in late-life depression: a cross-sectional study Part II Chapter 5 Apathy in remitted depression is not related to vascular risk. Chapter 6 Empirical support for the vascular apathy hypothesis: a structured review. Chapter 7 Strengths and weaknesses of the vascular apathy hypothesis: a narrative review. Chapter 8 Summary and general discussion. Appendices Nederlandse wetenschappelijke samenvatting Dankwoord Curriculum vitae 10 28 44 60 80 100 120 142 158 174 177

Chapter 1 Introduction

12 Vascular risk factors for depression and apathy Late-life depression Depression is one of the most common and disabling psychiatric disorders in later life. Box 1 presents the diagnostic criteria for a major depression. The prevalence of major late-life depression ranges between 0.9-9.4% for those living in private households and between 14-42% for those living in institutions 1, where it needs to be noted that subthreshold depression (i.e. when older adults suffer from depressive symptoms without meeting the full criteria for a major depression) is even more prevalent 2. The risk of becoming depressed in later life is raised in women and in individuals with a somatic illness, cognitive or functional impairment, lack or loss of social contacts and/or a history of depression 1. In fact, besides the risks that are particularly common in late life (e.g. somatic disease and functional and cognitive impairment), all risk factors for depression across a person’s lifespan can play a role in the development of late-life depression, also risk factors such as genetic predisposition, early life trauma and social stress that are typically associated with early-onset depression 3. In elderly persons coping with depression, particularly in those suffering from severe depression, chronic disease and loneliness, the risk of chronicity is higher than it is in younger depressed individuals 4. Antidepressant treatments, electroconvulsive therapy (ECT) and psychotherapy can be effective in older people 5, but often late-life depression goes unrecognized and untreated 6. In thosewho do receive treatment for their depression, older age, more severe and longer duration of the depression, comorbid anxiety, physical illness and executive dysfunction predict a worse outcome 7. The consequences of major and subthreshold depression in late life are severe: depressed elderly persons not only suffer from the depression itself, they also use more health care, particularly other types of health care than mental health care, and experience higher levels of functional and cognitive impairment and a lower quality of life, while their caregivers experience a high burden 8. Also, the risk of mortality is elevated in late-life depression 9, part of which is explained by a raised cardiovascular 10 11 and cerebrovascular mortality 12.

13 1 Vascular risk factors for depression and apathy Depression diagnostic criteria (DSM-5) The individual must be experiencing five or more symptoms during the same 2-week period and at least one of the symptoms should be either (1) depressed mood or (2) loss of interest or pleasure (core criteria). Collectively, these symptoms must cause clinically significant distress or impairment in social, occupational, or other important areas of functioning 1. Depressed mood most of the day, nearly every day. 2. Markedly diminished interest or pleasure in all, or almost all, activities most of the day, nearly every day. 3. Significant weight loss when not dieting or weight gain, or decrease or increase in appetite nearly every day. 4. Insomnia or hypersomnia nearly every day. 5. A slowing down of thought and a reduction of physical movement (observable by others, not merely subjective feelings of restlessness or being slowed down). 6. Fatigue or loss of energy nearly every day. 7. Feelings of worthlessness or excessive or inappropriate guilt nearly every day. 8. Diminished ability to think or concentrate, or indecisiveness, nearly every day. 9. Recurrent thoughts of death, recurrent suicidal ideation without a specific plan, or a suicide attempt or a specific plan for committing suicide. Vascular depression or a depressive-executive subtype of late-life depression? This clustering of vascular risks, vascular disease and depression in later life that clinicians frequently observed was confirmed in large epidemiological studies of late-life depression, whose findings prompted research into the potential relationships between depression and cardio- and cerebrovascular disease 13. Objectives were to try and confirm that depression was a causal risk factor for vascular disease, and to identify the underlying pathophysiological mechanisms of this relationship. Another field of research focused on questions regarding the causes and consequences of the raised risk of a depressive disorder in post-myocardial infarction 14 and post-stroke patients 15. Could it be that, not only recognized but also unrecognized or ‘silent’ vascular disease was a risk factor for and even a cause of late-life depression, and, if so, through what mechanisms? Neuroimaging studies showed an association between white matter hyperintensities (WMH), a marker of cerebral small vessel disease (CSVD; for more details, see the CSVD and vascular apathy hypothesis section), and depression 16. Clinically, CSVDrelated depression was linked to executive dysfunction and therapy resistance, leading to the inception of the vascular depression hypothesis 17. The proposed pathophysiological mechanism for this vascular subtype of depression was disruption of the fronto-striatal pathways of the brain by CSVD 17.

14 Vascular risk factors for depression and apathy Research into biological aging processes promoted a further differentiation of late-life depression syndromes, and provided information about the biomarkers with which they can be distinguished 18 (see Table1). The depression-executive dysfunction subtype of late-life depression is the only subtype that has been related to vascular risk and vascular disease and a higher risk of dementia 19. In clinical practice and compared to depressed older adults without executive deficits, those with the depression-executive dysfunction syndrome more often present with reduced fluency, impaired visual naming, paranoia, loss of interest in activities, and psychomotor retardation but with a milder vegetative syndrome 20. Moreover, treatment response is lower and the rate of recurrence is higher. Still, comprising antidepressants, ECT and/or psychotherapy, in essence treatment regimens for this subtype do not differ from those prescribed for a general depressive disorder 5. Moreover, since a distinct clinical syndrome and a causal relationship between CSVD and depression could not be established, the name ‘vascular depression’ was abandoned by most researchers and clinicians 21 22. Table 1. Biomarkers and behavior associated with late-life depression subtypes Aging process Biomarkers Typical Phenotype Cerebral small vessel disease (CSVD) Systolic blood pressure Pulse wave velocity Vessel calcification White matter hyperintensities (WMH) Fractional anisotropy in fronto-striatal tracts Depressive-executive dysfunction Inflammation and dopamine depletion Interleukin-6 (IL-6) Tumor necrosis factor alpha (TNF-alpha) C-reactive protein Dopamine D1/D2 receptor density Dopamine transporter (DAT) activity Response to stimulation Inflammation, slowness Oxidative stress and mitochondrial aging F2 isoprostanes VO2 max Enzymatic activity IH MRS lactate IH MRS N-acetyl aspartate 31P MRS phosphocreatine Frailty, fatigue Adapted from: [18] Rutherford BR, Taylor WD, Brown PJ, Sneed JR, Roose SP. Biological Aging and the Future of Geriatric Psychiatry. J Gerontol A Biol Sci Med Sci 2017; 72:343–52. https://doi.org/10.1093/GERONA/GLW241. Although the association between WMH (as biomarkers for CSVD) and depression was confirmed in a meta-analysis 16, WMH are particularly related to those items of depression scales that gauge motivational problems such as loss of interest and psychomotor

15 1 Vascular risk factors for depression and apathy retardation23. Accordingly, several studies have suggested that it might not be the depressive disorder but rather comorbid apathy that is related to CSVD 24 and to executive dysfunction 25. Apathy Being part of many neurological and psychiatric diseases, apathy is a transdiagnostic symptom 26 but it can also be a stand-alone syndrome. Characterized by reduced activity, thought and emotions, it clearly overlaps with definitions of motivational constructs. The consequences of apathy are serious as it reduces quality of life 27 and causes more functional impairment 28, while increasing the caregiver burden 29 30. Apathy is, moreover, associated with a higher risk of incident cardiovascular disease, stroke and mortality 31 and dementia 32. Apathy diagnostic criteria (2018) CRITERION A: a quantitative reduction of goal-directed activity (behavioural, cognitive, emotional or social) in comparison to the patient’s previous level of functioning CRITERION B: at least 2 of the 3 following dimensions for at least 4 weeks B1 BEHAVIOUR AND COGNITION: reduced general level of activity; diminished persistence of activity; less interest or slow in making choices; less interest in external issues; less interest in own health and image B2 EMOTION: less spontaneous emotion; fewer emotional reactions to the environment; less concern about the impact of actions/feelings on others; less empathy; less use of verbal or physical expressions B3 SOCIAL INTERACTION: less spontaneous social initiative; less environmentally stimulated social interaction; decreased interest in interactions with family members; less verbal interaction; being more homebound CRITERION C: These symptoms cause clinically significant impairment in functioning CRITERION D: The symptoms are not solely attributable to physical or motor disabilities, a diminished level of consciousness, substance use or major changes in the patient’s environment Adapted from: Robert P, Lanctôt KL, Agüera-Ortiz L, Aalten P, Bremond F, Defrancesco M, et al. Is it time to revise the diagnostic criteria for apathy in brain disorders? The 2018 international consensus group. Eur Psychiatry 2018; 54:71–6. https://doi.org/10.1016/J.EURPSY.2018.07.008.

16 Vascular risk factors for depression and apathy There are a number of validated scales to assess apathy across populations, of which the Neuropsychiatric Inventory (NPI) and the Apathy Evaluation Scale (AES) are the most robust 33. One of the problems that arise from the use in research, however, is that respondents with minimal cognitive impairment (MCI) or dementia tend to report lower apathy levels than peers without these health problems, which tendency is most likely attributable to less cognitive insight 34. Most researchers investigating cognitively impaired populations hence prefer to use clinician or caregiver reported scales. Research into apathy has also benefitted from more uniformity through the recent consensus on the diagnostic criteria for apathy 35, which can be used in neuropsychiatric as well as healthy populations. Applying these well-defined criteria 35 in a range of neuropsychiatric disorders, researchers documented apathy prevalences of 55% for Alzheimer’s disease, 70% for mixed dementia, 43% for minimal cognitive impairment, 27% for Parkinson’s disease, 53% for schizophrenia and 94% for major depressive disorder 26. Given that in the general population it is seen in 2-6%, apathy is predominantly a syndrome of old age, with the prevalence increasing with age, especially in men 36. Treatment options for apathy are primarily aimed at raising the activity level through external stimuli and at relieving the caregiver burden 37 since the evidence for the efficacy of pharmacological interventions in apathy is not well established and confined to specific populations. Thus, there is some evidence for the usefulness of methylphenidate for the treatment of apathy in patients with Alzheimer’s disease 38 and of dopamine agonists and rivastigmine in patients with Parkinson’s disease 39. The neuroscience of apathy Neuroimaging studies show that, across brain disorders, apathy is associated with abnormalities in the fronto-striatal pathways, most notably disruptions of the dorsal anterior cingulate cortex, the ventral striatum and connected brain regions 40. Functional MRI and diffusion tensor imaging (DTI) studies have revealed that when the disruption in these fronto-striatal pathways leads to disruption of the underlying reward network, higher levels of apathy are seen 41 (See Figure 1). Research into this reward network and its function in the motivation process is emerging 42. Studies combining functional MRI or DTI and behavioural paradigms show that the reward network plays a role in effortbased decision-making, i.e. the process in which a person decides whether to expend effort to gain a reward or not 42. In people with CSVD, apathy is associated with reduced connectivity in this specific network of the brain 43. CSVD and the vascular apathy hypothesis The prevalence of CSVD increases with age, from 5% in people aged 50 to almost 100% in those older than 90 years 44, with 52% of those with CSVD on neuroimaging showing apathy 24. CSVD refers to a group of atherosclerotic diseases of the small vessels of the brain causing ischaemic changes in the surrounding brain tissue. MRI-markers of CVSD include white matter hyperintensities (WMH), cerebral microbleeds, lacunar infarcts

17 1 Vascular risk factors for depression and apathy and visible perivascular spaces 45. Clinically, CSVD can be silent (without observable symptoms) or present as a variety of geriatric syndromes like cognitive impairment, bladder dysfunction, or problems with gait and balance. Individuals with CWVD have a higher incidence of depression, strokes, dementia, disability and death 44 45. Since apathy is associated with CSVD 24, and this association is independent of depression, the nature of this relationship has received increasing attention in the last few decades. This research has generated the vascular apathy hypothesis that expresses the notion that silent CSVD can cause apathy by disrupting the fronto-striatal pathways 46 47 48. Figure 1. Fronto-Striatal Pathway and Reward Network CSVD Cognition Subcortical vascular MCI / Subcortical vascular dementia  semantic memory  executive/attentional functioning  visuospatial functioning  perceptual skills Neuropsychiatric Vascular apathy?  emotion  thoughts  initiative Depressive‐executive sutype of depression loss of interest psychomotor retardation paranoia  fluency and visual naming Bladder dysfunction Gait Vascular parkinsonism postural instability falls parkinsonian‐ataxic gait Frontal cortex Nucleus accumbens Thalamus Basal ganglia Fronto-striatal pathway Reward network Figure 2. Proposed Clinical Symptoms of CSVD

18 Vascular risk factors for depression and apathy This model has given rise to new research questions. Is CSVD indeed a relevant causal risk-factor for apathy? Can CSVD be a sole cause of apathy and is CSVD-related apathy a recognizable and distinguishable clinical syndrome as using the term ‘vascular apathy’ suggests? These are all questions that lie at the heart of the research brought together in this doctoral thesis. Scope and objectives of the thesis Figure 3. Schematic representation of thesis outline The overall aim of the work presented here is to examine the associations between cerebrovascular disease with either depression or apathy in more depth. Figure 3 provides a schematic overview of the associations that are considered in the research documented in this thesis that consists of two parts. In the first part, we will be looking at the strength and nature of the relationships between cerebrovascular disease and depression and whether and how vascular risk and neuroticism interact in this relationship. In the studies presented in the second part, we investigate the strength and nature of the relationships between cerebrovascular disease, particularly CSVD, and apathy, where we evaluate the concept of vascular apathy as well as associations between CSVD and apathy in (remitted) depression. Part I In the study prescribed in Chapter 2 we asked ourselves: is depression associated with incident stroke and is this risk conditional upon the presence of cardiac disease? We sought to answer this question within the framework of the Longitudinal Aging Study Cardiovascular risk factors Cerebro- vascular accidents other vascular disease & Cerebral small vessel disease Chapter Depression Apathy Apathy in (remitted) depression Cardiac disease Neuroticism 2 4 3 5 7 6

19 1 Vascular risk factors for depression and apathy Amsterdam (LASA) in which depression as assessed at baseline is monitored and related to the incidence of stroke during a 9-year follow-up. We deemed this relevant as several studies have shown, albeit not consistently, that depression is a risk factor for stroke, 49 and because depression is not (yet) included as a well-established risk factor in stroke prevention guidelines 50. Of note here is that previous studies may have been limited by the measures they used to diagnose depression and/or stroke. And, even though cardiac disease is one of the main risk factors for stroke, none explored whether this putative risk is conditional upon the presence of cardiac disease. Our study tries to overcome these shortcomings by including cardiac disease as effect modifier, by taking depression severity and chronicity into account, and finally by assessing stroke using a composite measure based on self-report data, medical records of GPs and death certificates. In Chapter 3 the research question we posed was whether the risk of depression on future stroke is conditional upon depressive symptoms related to underlying vascular disease and not upon depressive symptoms associated with high neuroticism? This study was again conducted as part of LASA, extending the study reported on in Chapter 2. We now assume that vascular depression, defined as depression etiologically linked to vascular disease, increases the risk of stroke, where depression that is etiologically related to high neuroticism does not. If confirmed, the presence of underlying (silent) vascular disease could confound the association between depressive symptoms and stroke, which would then explain the differences observed in populations with cardiac disease and without cardiac disease. The objective of the study presented in Chapter 4 was to explore whether neuroticism and vascular disease interact as risk factors for depression? Since higher levels of neuroticism and vascular disease often co-occur in individuals coping with late-life depression, not only the impact of each of these vulnerability factors but also their interactions are of interest. We will be examining the presence and nature of such interactions in a population-based survey called the Nijmegen Biomedical Study (NBS). Since neuroticism aggravates the impact of life events and has been related to a poorer adherence to (vascular) treatment we expect to find a positive interaction by which neuroticism exacerbates the impact of vascular disease on depression Part II In the second part of this thesis, the focus is on associations between cerebrovascular disease and apathy. In the study reported in Chapter 5 our aim was to elucidate whether apathy after remitted depression is related to cerebral small vessel disease (CSVD)? We anticipated to find associations between the severity of apathy and vascular risk factors and diseases in adults with a remitted depressive disorder who participated in the Netherlands Study of Depression and Anxiety (NESDA) and the Netherland Study of Depression in Older Persons (NESDO). We assumed that this association would not be explained by the residual symptom of a depressed mood, which we explicitly corrected for.

20 Vascular risk factors for depression and apathy Chapter 6 comprises a systematic review of studies investigating whether subclinical CSVD is associated with apathy in the general population? Apathy studies will be included in which CSVD is defined as white matter hyperintensities (WMH) or white matter diffusivity changes, lacunar infarcts, cerebral microbleeds, decreasing cortical thickness and/or perivascular spaces. We also considered studies with peripheral proxies for CSVD, i.e. the ankle brachial index, intima media thickness, cardio-femoral pulse wave velocity, hypertension or cardiovascular disease. Our final study presented in Chapter 7 explores whether CSVD can be a (sole) cause of apathy? The vascular apathy hypothesis is evaluated in depth in a narrative review in which the Bradford-Hill criteria are applied to distinguish between association and causation. We will use the results to determine whether vascular apathy can indeed be considered a distinct clinical syndrome, while reflecting on the pros and cons of the use of the term ‘vascular apathy’.

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24 Vascular risk factors for depression and apathy 41. Tay J, Tuladhar AM, Hollocks MJ, et al. Apathy is associated with largescale white matter network disruption in small vessel disease. Neurology. 2019;92(11):E1157-E1167. doi:10.1212/ WNL.0000000000007095 42. Pessiglione M, Vinckier F, Bouret S, Daunizeau J, Le Bouc R. Why not try harder? Computational approach to motivation deficits in neuro-psychiatric diseases. Brain. 2018;141(3):629-650. doi:10.1093/BRAIN/AWX278 43. Lisiecka-Ford. DM, Tozer DJ, Morris RG, Lawrence AJ, Barrick TR, Markus HS. Involvement of the reward network is associated with apathy in cerebral small vessel disease. J Affect Disord. 2018;232:116-121. doi:10.1016/J. JAD.2018.02.006 44. Cannistraro RJ, Badi M, Eidelman BH, Dickson DW, Middlebrooks EH, Meschia JF. CNS small vessel disease: A clinical review. Neurology. 2019;92(24):1146-1156. doi:10.1212/WNL.0000000000007654 45. Shi Y, Wardlaw JM. Update on cerebral small vessel disease: a dynamic wholebrain disease. Stroke Vasc Neurol. 2016;1(3):83-92. doi:10.1136/SVN-2016000035 46. Ligthart SA, Richard E, Fransen NL, et al. Association of vascular factors with apathy in community-dwelling elderly individuals. Arch Gen Psychiatry. 2012;69(6):636-642. doi:10.1001/archgenpsychiatry.2011.1858 47. Marijnissen RM, Bus BAA, Schoevers RA, et al. Atherosclerosis decreases the impact of neuroticism in late-life depression: Hypothesis of vascular apathy. Am J Geriatr Psychiatry. 2014;22(8):801-810. doi:10.1016/j.jagp.2013.01.001 48. Wouts L, Kessel M van, Beekman ATF, Marijnissen RM, Voshaar RCO. Empirical support for the vascular apathy hypothesis: A structured review. Int J Geriatr Psychiatry. 2020;35(1):3-11. doi:10.1002/GPS.5217 49. Van der Kooy K, van Hout H, Marwijk H, Marten H, Stehouwer C, Beekman A. Depression and the risk for cardiovascular diseases: systematic review and meta analysis. Int J Geriatr Psychiatry. 2007;22(7):613-626. doi:10.1002/ GPS.1723 50. Goldstein LB, Adams R, Alberts MJ, et al. Primary prevention of ischemic stroke: a guideline from the American Heart Association/American Stroke Association Stroke Council: cosponsored by the Atherosclerotic Peripheral Vascular Disease Interdisciplinary Working Group; Cardiovascular Nursing Council; Clinical Cardiology Council; Nutrition, Physical Activity, and Metabolism Council; and the Quality of Care and Outcomes Research Interdisciplinary Working Group: the American Academy of Neurology affirms the value of this guideline. Stroke. 2006;37(6):1583-1633. doi:10.1161/01. STR.0000223048.70103.F1

25 1 Vascular risk factors for depression and apathy

Part I

Vascular risk factors for depression and apathy | Part 1 28 Chapter 2 Cardiac disease, depressive symptoms, and incident stroke in an elderly population Lonneke Wouts, MD; Richard C. Oude Voshaar, MD, PhD; Marijke A. Bremmer, MD; Jan K. Buitelaar, MD, PhD; Brenda W. J. H. Penninx, MD, PhD; Aartjan T. F. Beekman, MD, PhD Arch Gen Psychiatry. 2008;65(5):596-602. doi:10.1001/archpsyc.65.5.596

Part 1 | Vascular risk factors for depression and apathy 29 2

Vascular risk factors for depression and apathy | Part 1 30 Abstract Context Previous research suggests that depression is a risk factor for stroke. However, the reliability of much research is limited by the lack of documentation on the presence of preexistent cardiovascular disease and by the use of limited measures of depression or stroke. Objectives To test the hypotheses that (1) clinically relevant depressive symptoms are an independent risk factor of incident stroke in cardiac and noncardiac patients and (2) more chronic and severe depressive symptoms are associated with incident stroke. Design A cohort of elderly Dutch people (aged ≥ 55 years) was followed up for 9 years in the Longitudinal Aging Study Amsterdam (baseline measurements were taken in 1992 or 1993, and the study concluded in 2001 or 2002, respectively). Setting General community. Participants Randomly selected population-based sample (N = 2965) without a history of stroke. Main Outcome Measures The study end point was a first stroke (nonfatal or fatal). Depression was measured using the National Institute of Mental Health Diagnostic Interview Schedule and the Center for Epidemiological Studies–Depression Scale. Multivariate Cox proportional hazards regression analyses of stroke incidence were performed. The association of the chronicity and severity of depressive symptoms was studied in extended models with time-dependent variables. Results The sample’s mean (SD) age was 70.5 (8.7) years, 52.1% were women, and the mean (SD) follow-up was 7.7 (3.1) years. Inclusion of an interaction between cardiac disease and clinically relevant depressive symptoms improved the model for stroke (P = .03). In participants with preexistent cardiac disease, but not in participants without cardiac disease, clinically relevant depressive symptoms at baseline (hazard ratio [HR], 2.18; 95% confidence interval [CI], 1.17-4.09) and the severity (range, 0-60; HR, 1.08; 95% CI, 1.021.13) and chronicity (HR, 3.51; 95% CI, 1.13-10.93) of symptoms during follow-up were associated with stroke. Conclusions Preexistent cardiac disease moderates the association between depressive symptoms and incident stroke. In cardiac patients, baseline depressive symptoms and both the severity and chronicity of symptoms during follow-up are associated with incident stroke.

Part 1 | Vascular risk factors for depression and apathy 31 2 Introduction Depression is highly prevalent among elderly individuals, with a reported prevalence in the community of 1.8% for major depression, 9.8% for minor depression, and 13.5% for clinically relevant depressive symptoms (CRDSs)1. Although cross-sectional studies2 3. have shown depression to be associated with poor health, functional impairment, decreased quality of life, and greater use of health services, prospective studies4 have shown depression and depressive symptoms to be independent determinants of mortality. Recently, myocardial infarction was shown to be a mediator of the higher mortality of depressed individuals5 6. The biological pathways hypothesized to link depression with cardiovascular disease include sympathetic nervous system activation, dysregulation of the hypothalamic-pituitary-adrenocortical axis, platelet aggregation dysfunction, and inflammation7 8. Studies investigating whether depression is also a risk factor for the development of cerebrovascular events have yielded mixed results. The recent consensus guideline of the American Heart Association and the American Stroke Association for the prevention of cerebrovascular events does not mention depression as a possible risk factor for stroke9. In a recent meta-analysis,5 the pooled relative risk of stroke in those with a depressed mood was 1.4 (range, 1.2-1.8), but this estimated risk was influenced by the methodologic shortcomings and heterogeneity of the studies included. In particular, most of the early studies used limited measures of depression, with only 2 using the DSM-IV to diagnose depression. The first of these studies used self-reported data on the occurrence of stroke, and the second used physician-reported ICD-10–classified cardiovascular disease10 11. Neither study documented the chronicity and severity of depression. Another source of heterogeneity in studies of the relationship between depressive symptoms and stroke is the possible moderating effect of cardiac disease. Because cardiac disease is an important predictor of stroke, stratifying by cardiac disease divides the population into low- and high-risk populations. If one assumes that the pathophysiologic mechanisms are comparable to those leading to cardiovascular disease in depressed individuals, depression in cardiac patients could aggravate the existing atherosclerotic disease, ultimately leading to stroke. Furthermore, the prevalence and incidence of depression would be expected to be higher in cardiac patients based on the vascular depression hypothesis, which states that subclinical underlying cerebrovascular disease may cause depression12 13 14 15 16. According to this hypothesis, underlying atherosclerotic disease could give rise to both stroke and depression in cardiac patients. Bearing in mind these sources of heterogeneity in earlier studies, we investigated whether the presence, severity, and chronicity of depressive symptoms and major depressive disorder (MDD) are independently associated with incident stroke in elderly patients with or without cardiac disease during a 9-year follow-up.

Vascular risk factors for depression and apathy | Part 1 32 Methods Study design and population This study was conducted within the Longitudinal Aging Study Amsterdam (LASA), which is a prospective cohort study of Dutch people aged 55 to 85 years. The LASA started in 1992, and its methods have been described in detail elsewhere 17 18. The general aim of LASA was to study the autonomy and well-being of an aging population. A randomly selected age- and sex-stratified sample (according to expected mortality figures) was drawn from the population registers of 11 municipalities in the Netherlands. The reason for this relative oversampling of older old people (both men and women) and elderly men was to compensate for an anticipated higher unavailability for follow-up among physically frail people. The initial response rate was 62.3%, and nonresponse was associated with age, sex, and urbanicity. The sample first took part in the cross-sectional NESTOR–living arrangements and social networks study 19 and was later interviewed and followed up every 3 years in LASA; 81.7% of the NESTOR–living arrangements and social networks study population participated in LASA, with nonresponse being related to age but not to sex. All interviews were recorded for quality control purposes. All LASA participants without a history of stroke at the baseline measurement were eligible for inclusion (n = 3018). Participants in whom depressive symptoms (51 [1.6%]) or stroke (2 [0.06%]) were not evaluated at baseline were excluded. The remaining 2965 individuals participated in this study of the association among depressive symptoms, CRDSs, or MDD at baseline and incident stroke in patients with or without cardiac disease at baseline. The mean (SD) follow-up was 7.7 (3.1) years; participants were assessed at baseline and every 3 years. For the extended Cox proportional hazards regression analyses, we required the availability of a baseline and at least 1 follow-up assessment of depression. In total, 412 participants (13.9%) were excluded because they had died or had a stroke before the first follow-up interview, and 328 participants (11.1%) were excluded because they never had a follow-up assessment of depressive symptoms. Unavailability for follow-up of depressive symptoms was associated with an older age, a lower score on the Mini-Mental State Examination (MMSE), more functional limitations, and cardiac disease (P < .001 for all). The mean (SD) follow-up for the remaining 2225 participants was 9.1 (1.7) years, with a mean (SD) number of 3.4 (0.8) measurements of depressive symptoms. Measurements Stroke Morbidity and Mortality The study end point was the first occurrence of stroke (fatal or nonfatal). Nonfatal strokes were established based on self-report during the 3-yearly interviews and information obtained from general practitioners (GPs) in response to questionnaires sent in 19921993, 1995-1996, and 2000-2001. The GPs were asked whether a participant had ever been diagnosed as having a cerebrovascular accident, the year in which it occurred, and whether a specialist had confirmed the diagnosis. Previous research in LASA had shown

Part 1 | Vascular risk factors for depression and apathy 33 2 such self-reported information to be moderately accurate (concordance with GP: κ = 0.56; 95% confidence interval [CI], 0.48-0.64) 20. Therefore, we considered a stroke to have occurred if the self-reported and GP information were consistent or if a cardiac specialist confirmed the GP diagnosis of stroke. Death due to stroke was established based on death certificates registered by the Netherlands Central Bureau of Statistics. Death certificates of deceased participants were 100% complete. Stroke was defined as ICD-9 codes 431, 433, 434, and 436 and ICD-10 codes I-61, I-63, and I-64. The event was timed as occurring in the year halfway between the 3-yearly assessments for nonfatal strokes and as the year of death for fatal strokes. Depression Depressive symptoms were measured using the Center for Epidemiological Studies– Depression Scale (CES-D). This is a widely used instrument to measure depressive symptoms in the community 21. In LASA, the traditional cutoff of the CES-D of 16 or greater had a sensitivity of 100% and a specificity of 88% for MDD 22. Major depressive disorder was diagnosed using the National Institute of Mental Health Diagnostic Interview Schedule (DIS) 23. Subthreshold depressive disorder (SDD) was diagnosed if a study participant scored 16 or higher on the CES-D but did not meet DSM-III diagnostic criteria for MDD on the DIS. The SDD category included 107 respondents with a CES-D score of 16 or higher but no available DIS diagnosis. We use the term CRDSs were refer to the broad category of MDD or SDD, and we use the term depressive symptoms to refer to the score on the CES-D (range, 0-60). The DIS and CES-D were completed every 3 years, which made it possible to estimate the mean severity of depressive symptoms and the chronicity of CRDSs and MDD during the follow-up. The mean severity of depressive symptoms was defined as the mean CES-D score of all observations until the year of the first stroke or censoring divided by the total number of observations in this interval. The chronicity of MDD was defined as the total number of observations of MDD until the year of the first stroke (or censoring) divided by the total number of observations in this interval. The chronicity of CRDSs was the total number of observations of an MDD or a score on the CES-D of 16 or higher until the year of the first stroke (or censoring) divided by the total number of observations in this interval. Cardiac Disease Cardiac disease was defined as myocardial infarction, congestive heart failure, angina pectoris, or cardiac arrhythmia and established at baseline using an algorithm used earlier in LASA6. This algorithm uses 3 sources of information: self-reported, medication, and GP information. We considered only 1 confirmative source necessary for diagnosis because self-reported cardiac disease is sufficiently accurate in LASA (concordance with GP: κ = 0.69; 95% CI, 0.65-0.73) 20. We used a broad definition of cardiac disease because although it could lead to a type II error (overcorrection), the use of a more restricted definition could lead to a type I error (undercorrection), and we preferred to use the broader category.

Vascular risk factors for depression and apathy | Part 1 34 Confounders Sociodemographic variables (sex and age), general health-related variables (functional limitations and cognitive impairments), and important stroke risk factors (diabetes mellitus, smoking, hypertension, and obesity) were included in the analyses as potential confounders. The number of functional limitations was scored with a 3-item questionnaire 24 as none, 1, or 2 or more. Cognitive impairments were measured with the MMSE 25. A history of diabetes mellitus was considered present if reported by the respondent, if the person used antidiabetic agents, or if a GP confirmed the diagnosis. The variable smoking included current smoking. Blood pressure was measured every 3 years, preferably from the arm but otherwise from the fingertip. Hypertension was categorized into stage 1 hypertension (a mean systolic blood pressure of 140-159 mm Hg or a mean diastolic blood pressure of 90-99 mm Hg) and stage 2 hypertension (a mean systolic blood pressure of ≥ 160 mm Hg or a mean diastolic blood pressure of ≥ 100 mm Hg) 26. Obesity was defined as a body mass index (calculated as weight in kilograms divided by height in meters squared) of 30 or greater 27. Antidepressant use was established by asking about the use of medication and by visually checking all of the participants’ medications at each 3-yearly assessment. Statistical analyses All primary variables and covariates were checked for normality, collinearity, and proportionality of hazards. Missing data for covariates were restored by imputation of the most reported value, and the results for analyses with or without imputed data were checked for differences 28. Baseline characteristics for participants with or without depressive symptoms were compared using χ2 and t tests. Univariate Cox proportional hazards analyses of first strokes were conducted for primary and secondary variables. Models of stroke incidence, which included interaction terms of depression variables (depressive symptoms, CRDSs, and MDD) by cardiac disease status, were tested by multivariate Cox proportional hazard regression analyses. Subsequently, the sample was stratified for cardiac disease, and the relationship between depression variables and incident stroke was examined by multivariate Cox proportional hazard regression analysis. We used extended Cox proportional hazard models to examine the association between the severity of depressive symptoms or the chronicity of CRDSs or MDD and incident stroke, with these depression variables and possible confounders as time-dependent variables 29. Results Baseline characteristics The mean (SD) age of the 2965 elderly study participants (52.1% female) was 70.5 (8.7) years, and 39.6% had 1 or more functional limitations (Table 1). At baseline, 58 (2.0%) had MDD and 372 (12.5%) had SDD. Myocardial infarction was reported in 285 (9.6%), congestive heart failure in256 (8.7%), angina pectoris in283 (9.5%), and cardiac arrhythmia in 132 (4.4%). The CRDSs at baseline were associated with older age (P < .001), female sex (P < .001), more functional limitations (P < .001), poorer performance on the MMSE (P < .001), smoking (P = .04), diabetes mellitus (P = .03), and cardiac disease (P < .001).

Part 1 | Vascular risk factors for depression and apathy 35 2 Table 1. Baseline Characteristics Characteristic ValueA Age, mean (SD), y 70.5 ( 8.7) Abbreviations: CRDSs, clinically relevant depressive symptoms, MDD, major depressive disorder, MMSE, Mini-Mental State Examination. A Data are presented as number (percentage) of participants (N=2965) unless otherwise indicated. B The range was from 0 to 30. MMSE score, mean (SD)B 27.0 (2.9) MDD 58 (2.0) CRDS 430 (14.5) Women 1546 (52.1) Functional limitations ≥1 1173 (39.6) Smoking 648 (21.9) Hypertension stage 1 or 2 623 (21.0) Cardiac disease 611 (20.6) Diabetes mellitus 358 (12.1) Obesity 457 (15.4) The overall rate of stroke was 7.7 per 1000 person-years: the rate of first nonfatal stroke was 2.8 per 1000 person-years, and the rate of fatal stroke was 4.9 per 1000 person-years. The rate of incident stroke was higher, but not significantly so, among participants with CRDSs at baseline (P = .10), as shown in Table 2. On univariate analysis, cardiac disease at baseline (P < .001), older age (P < .001), poorer MMSE performance (P < .01), more functional limitations (P < .01), diabetes mellitus (P < .001), and hypertension (P < .001) were associated with a higher incidence of stroke. The use of antidepressants (49 participants [1.7%]) was not associated with incident stroke (hazard ratio [HR], 0.35; 95% CI, 0.05-2.52; P = .30). Table 2. Stroke Rates and Univariate Cox Regression on Incident Stroke Variable No. of Strokes per 1000 Person-years Wald statistic HR (95% CI) P value CRDS no 7.4 yes 10.11 2.645 1.39 (0.94-2.1) .10 Cardiac disease no 6.7 yes 11.9 11.91 1.78 (1.28-2.47) <.001 Abbreviations: CI, confidence interval; CRDS, clinically relevant depressive symptoms; HR, hazard ratio